Tuberculosis resistance prediction method

ABSTRACT

The invention relates to a method for predicting mycobacterial drug resistance by isolating mycobacterial nucleic acid from a sample, obtaining a sample sequence from the nucleic acid, aligning and comparing the sample sequence to a reference sequence and determining for each reference position whether the sample sequence value is the same as a particular sequence value assigned to the position in a table. If both values are the same, a position weight value is assigned to the position. A predictor value is obtained by adding all position weight values and the predictor value is compared to a threshold value. If the predictor value is smaller than the threshold value, drug resistance is predicted. The invention encompasses a system for practicing the method, and the use of certain antibacterial drugs to treat infections by pathogens, resistance of which has been determined by the method of the invention.

The present invention relates to a method for predicting the resistance of a mycobacterial pathogen to common antibacterial drugs.

BACKGROUND OF THE INVENTION

Tuberculosis (TB) is caused by Mycobacterium tuberculosis. According to the World Health Organisation, about one-quarter of the world's population has latent TB, associated with a 5-15% lifetime risk of falling ill with TB. Patients with compromised immune systems, such as people living with HIV, malnutrition or diabetes, or people who use tobacco, have a much higher risk of falling ill. As a result, TB is one of the top 10 causes of death worldwide. In 2017, 10 million people fell ill with TB, and 1.6 million died from the disease (including 0.3 million among people with HIV).

Anti-TB drugs have been used for decades and strains that are resistant to 1 or more of the most common drugs have been found throughout the world. Drug resistance emerges when drugs are used inappropriately, through incorrect prescription by health care providers, poor quality drugs, and patients stopping treatment prematurely.

Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin. MDR-TB is treatable and curable by using second-line drugs. However, second-line treatment options are limited and require extensive chemotherapy with drugs that are expensive and toxic. Extensively drug-resistant TB (XDR-TB) is a more serious form of MDR-TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs, often leaving patients without any further treatment options. MDR-TB remains a public health crisis and a health security threat. WHO estimates that in 2017 there were 558 000 new cases with resistance to rifampicin—the most effective first-line drug—of which 82% had MDR-TB. About 8.5% of MDR-TB cases had extensively drug-resistant TB (XDR-TB).

Worldwide, only 55% of MDR-TB patients are currently successfully treated. In 2016, WHO approved the use of a short, standardised regimen for MDR-TB patients who do not have strains that are resistant to second-line TB medicines. This regimen takes 9-12 months and is much less expensive than the conventional treatment for MDR-TB, which can take up to 2 years. Patients with XDR-TB or resistance to second-line anti-TB drugs cannot use this regimen, however, and need to be put on longer MDR-TB regimens.

The objective of the present invention is to provide improved methods to genetically analyse drug resistance and predict drug resistance or susceptibility in mycobacteria, thereby enabling rapid identification of response profiles in TB patients, and administration of an adequate drug regime to the patient. This objective is attained by the subject matter of the independent claim.

DESCRIPTION

For the purpose of diagnosing patients with suspected tuberculosis the inventors first determined from a literature search which genes on the genomes of the Mycobacterium tuberculosis complex (MTBC) members have mutations that are predictive for resistance against 17 antibiotics. The inventors employed commercially available primers and probes to amplify the full length genes containing the specific mutations required for the resistance prediction. These specific mutations were predicted through machine learning, validated experimentally and form the present invention.

Several molecular diagnostics approaches based on DNA/RNA analysis (Real Time PCR, Microarray, digital PCR) or protein analysis (Mass Spectrometry) are currently being used in routine diagnostics or are under development. These approaches identify a small number of genes or variants that are unique to the pathogen and are responsible for giving rise to resistance phenotype. They are usually fast and accurate.

Whole genome sequencing of the Mycobacterium genome is currently performed in specialized reference centres with the purpose of identification of new resistance genes/gene variants and to monitor the spread of strains. It usually requires preculture of the bacteria. Whole genome sequence has not yet entered the realm of routine TB diagnostics. Methods have been published for the analysis of whole genome data, including resistance prediction, which consider only a limited number of genes, making them useful only as a supplementary to the culture-based diagnostics. There is currently no molecular approach that can precisely predict susceptibility for all or at least a majority of the relevant antibiotic drugs from the genetic information generated from a molecular assay, therefore molecular diagnostics so far cannot suggest an antibiotic therapy. Whole genome sequencing approaches are largely limited to research activities and not yet translated to routine diagnostics due higher costs than current alternatives as well as lack of CE-IVD certified diagnostic software to interpret the whole genome sequencing data.

Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods to genetically analyse drug resistance and predict mycobacterial drug susceptibility or mycobacterial drug resistance in a patient.

This objective is attained by the subject-matter of the independent claims of the present specification.

Terms and Definitions

In the context of the present specification, the term nucleotides refers to nucleic acid or nucleic acid analogue building blocks, oligomers of which are capable of forming selective hybrids with RNA or DNA oligomers on the basis of base pairing. The term nucleotides in this context includes the classic ribonucleotide building blocks adenosine, guanosine, uridine (and ribosylthymine), cytidine, the classic deoxyribonucleotides deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine and deoxycytidine. It further includes analogues of nucleic acids such as phosphotioates, 2′O-methylphosphothioates, peptide nucleic acids (PNA; N-(2-aminoethyl)-glycine units linked by peptide linkage, with the nucleobase attached to the alpha-carbon of the glycine) or locked nucleic acids (LNA; 2′O, 4′C methylene bridged RNA building blocks). The hybridizing sequence may be composed of any of the above nucleotides, or mixtures thereof.

In the context of the present invention, the term sequencing refers to the determination of the nucleotide sequence of an amplified nucleic acid obtained—for example by polymerase chain reaction (PCR), particularly multiplex PCR—from a mycobacterial nucleic acid sample. Various methods are known in the art, sequencing can be carried out using conventional or next generation sequencing, (e.g. Sanger dideoxy, Illumina, IonTorrent, Nanopore).

In the context of the present invention the term position comparison value is a numerical value that is assigned to a reference position (as specified above) by comparison of a nucleic acid sample sequence to a nucleic acid reference sequence.

One example for comparison of nucleic acid sequences is the BLASTN algorithm that uses the default settings: Expect threshold: 10; Word size: 28; Max matches in a query range: 0; Match/Mismatch Scores: 1.-2; Gap costs: Linear. Unless stated otherwise, sequence identity values provided herein refer to the value obtained using the BLAST suite of programs (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) using the above identified default parameters for protein and nucleic acid comparison, respectively. Methods for alignment of sequences for comparison are well-known in the art. Alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482 (1981), by the global alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Nat. Acad. Sci. 85:2444 (1988) or by computerized implementations of these algorithms, including, but not limited to: CLUSTAL, GAP, BESTFIT, BLAST, FASTA and TFASTA. Software for performing BLAST analyses is publicly available, e.g., through the National Center for Biotechnology-Information (http://blast.nci.nlm.nih.gov/).

SUMMARY OF THE INVENTION

The present invention demonstrates a method to diagnose patients with tuberculosis infection and guide optimal therapy by predicting susceptibility or resistance to several antibiotics typically used in treating tuberculosis patients. The method is based on sequencing key regions from the genome of the tuberculosis strain extracted from the patient sample. Contrary to the current standard of care, culturing Tb strains in presence of antibiotics (called phenotypic testing), which takes several weeks, the present method is faster (24-48 hours depending on the protocol) while delivering the same information on drug susceptibility or resistance. Compared with other molecular based assays, such as GenXpert or Hain MTBDR+, the method of the invention includes more key regions on the DNA and can thus provide more and better treatment options. In general, the method makes use of key positions on the DNA of M. tuberculosis complex that were previously not known to be associated with drug resistance or susceptibility. These new positions in turn improve the prediction accuracy of drug resistance or susceptibility. Given a method to interrogate particular positions on the genome of M. tuberculosis (e.g. using whole-genome sequencing or targeted sequencing or PCR+sanger sequencing) the state of the art prediction method will look for any mutation known to be associated with drug resistance or susceptibility from the ReSeqTB database (e.g. from http://erj.ersjournals.com/content/50/6/1701354). If any mutation known to be associated with resistance to a particular drug is found, that isolate is predicted to be phenotypically resistant to that drug. If any mutation conferring susceptibility is found, or the sequence corresponds to wild-type M. tuberculosis, or contains only phylogenetic mutations, then the isolate is predicted to be phenotypically susceptible to that drug (as described in N Engl J Med 2018; 379:1403-1415). The present method improves upon this algorithm, by giving each mutation from a list of relevant mutations a specific weight and then comparing this weighted sum to a pre-determined threshold. This list includes far more positions than known in the art at present, and significantly exceeds those known from the ReSeqTB database. If the sum is above the threshold, the isolate will be predicted to be phenotypically susceptible to the drug, and if the sum is equal or below the threshold, it will be predicted as phenotypically resistant to this drug. The pre-determined threshold and list of mutations included in the sum and the weights are specific for each drug (see Tables A through Q). Together they determine the accuracy of the present method in predicting drug susceptibility or resistance compared to the phenotypic result obtained with the above-mentioned culture method. Furthermore, the current publicly available datasets only contain graded mutations against 13 drugs while the here presented invention also contains mutations and appropriate weights for 4 additional drugs: Ciprofloxacin, para-aminosalycylic acid, cycloserine and rifabutin.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to a method for predicting mycobacterial susceptibility or resistance to an antibacterial drug in a patient. This method comprises the following steps:

Mycobacterial nucleic acid is isolated from a sample.

In a sequencing step, a nucleic acid sample sequence is obtained from said mycobacterial nucleic acid.

In a subsequent alignment step, the sample sequence is aligned to a reference sequence, which for the purpose of the present invention is the sequence NC_000962.3 (Mycobacterium tuberculosis H37Rv, complete genome). The reference sequence comprises a plurality of reference positions (RN). In the below Tables, the reference positions (RN) are characterized by their number in the reference sequence; the number of the position is given in the column designated (POS) identified at the top of Tables A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P and/or Q. Each drug for which a prediction is enabled by the method of the invention is associated to a different table; the drug is identified at the top of the table.

The alignment step yields a sample sequence value S^(R) for each of the reference positions, in other words, the sample sequence value S^(R) is the true sequence value (one of A, T, G, C referring to adenine, thymidine, guanine and cytosine, respectively) of the sample sequence.

The sequencing step is designed to obtain a sample sequence capable of aligning to all of the positions identified in the respective table selected from Tables A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P and/or Q that is associated to the drug of interest. For embodiments that are aimed at determining drug susceptibility for a plurality, or for all, of the antibacterial drugs of Tables A to Q, the sequencing step needs to be designed to allow aligning to all of the positions in the tables associated with the drugs of interest.

In a subsequent comparison step, the sample sequence obtained in the sequencing step is compared to the reference sequence in at least 90%, particularly ≥95%, of said plurality of reference positions (POS) identified in the one table or several tables, as the case may be, selected from Tables A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P and/or Q. For each reference position in the table, it is determined whether the sample sequence value S^(R) (the real sequence value at the respective position of the sample sequence) is the same as the sample sequence value S^(N) (the sequence value given under the header S^(N), to be distinguished from S^(R) and R^(N)) assigned to said position in said table.

If S^(R) is the same as S^(N) (the value given in the predictor table), the value (W) associated to S^(N) in the table is assigned as the position weight value to the position.

If S^(R) is not the same as S^(N), the value 0 (zero) is assigned as the position weight value to the position.

Thereby, a position weight value assigned to each of said reference positions is obtained. Each of the position weight values is associated and useful only with reference to the antibacterial drug designated in the table from which the position weight values are derived.

In other words, for each of the positions given in a column headed by POS in any of Tables A to Q, which have the value R^(N) in the reference sequence (with R^(N) designated in the entry just right of the position number in the table), the real sample sequence value S^(R) is determined and compared to the sample value S^(N) in the entry to the right of R^(N) in the table. If S^(R) and S^(N) are the same, then the position weight value W given just to the right of S^(N) is noted for the position. If S^(R) and S^(N) are not the same, then the position weight value W for this position is zero.

The denominators R^(N) and S^(N) are written without superscript (RN/SN) in the tables for better legibility.

A predictor value to predict resistance against said antibacterial drug designated in said table, is then obtained by adding all position weight values obtained in the comparison step to obtain the predictor value. In other words, all position weight values obtained from one table are added to give a predictor value associated to the particular drug associated to the table.

Subsequently, the predictor value is compared to the threshold value identified in the header of said table. If the predictor value is equal or smaller than the threshold value, resistance to the antibacterial drug is predicted. Alternatively, if the predictor value is larger than the threshold value, susceptibility to the antibacterial drug is predicted.

Sampling

The sample had previously been obtained from the patient or an object associated with the patient. While the patient's involvement in the sampling is not implied or necessary, it is to be emphasized that the method is directed at obtaining information about mycobacterial pathogens directly associated to one particular patient in order to predict treatment outcomes for particular drugs in the patient.

In the context of the present specification, the term sample may refer to (inter alia) a swab sample, tissue, body fluids (such as urine, saliva, blood), a cell containing sample, a biopsy sample and clinical patient isolates, any of which are expected to comprise at least one mycobacterial nucleic acid molecule.

Alternatively, the sample may be derived from a clinical setting not associated with a particular patient, but with a plurality of potential patients. Examples may be sample swabs obtained as part of a mycobacterial control effort in clinics, prisons, public transport settings etc.

Sequencing

Many methods are known to the skilled artisan to arrive at a nucleic acid sequence representative of the mycobacterium expected to be present in the sample. Current approaches include, but are not limited, to massively parallel sequencing methods sometimes summarized under the header of “next generation sequencing” (NGS). The skilled person understands that for the purposes of the present invention, the method of amplification, where appropriate, and the method of sequencing can be selected according to the circumstances, as long as the obtained sequence(s) allow alignment of the sequence that is representative of the sample with the reference sequence.

In certain embodiments, the comparison step comprises comparing said sample sequence to said reference sequence in each of said plurality of reference positions (POS) identified in said table. The skilled person understands that while the greatest possible accuracy of the method is only attained by visiting each and all positions of a given table, omitting a relatively small number of positions, particularly a small number of positions associated with the lowest absolute values of W, will not necessarily impact the accuracy of the method to the point of making it useless, or even making it only as useful as prior art methods for predicting resistance.

In certain embodiments, resistance or susceptibility to an antibacterial drug is determined for more than one drug by performing the method comparing the sample sequence to more than one of Tables A to Q.

In certain embodiments, drug resistance or susceptibility is determined for six antibacterial drugs, particularly for eight antibacterial drugs, more particularly for ten or twelve, or even for fourteen or sixteen antibacterial drugs.

In certain embodiments, drug resistance or susceptibility is determined for a plurality of antibacterial drugs including at least one, particularly two, three or even all of ciprofloxacin, para-aminosalycylic acid, cycloserine and rifabutin.

In certain embodiments, drug resistance is determined for isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, ciprofloxacin, moxifloxacin, ofloxacin, amikacin, capreomycin, kanamycin, prothionamide, Ethionamide, para-aminosalicylic acid, cycloserine, rifabutin and levofloxacin.

A second aspect of the invention relates to a system comprising a sequencing means and a computer programmed to carry out the method of any one of the embodiments of the first aspect of the invention. The sequencing means can be an automated sequencer. It is understood that the isolation step is not necessarily performed by the system, but the steps of sequencing, alignment, comparison and summation of the position weight values with subsequent prediction can be performed automatically.

Another aspect of the invention relates to a method of treatment or a use of an antibacterial drug in treatment of a mycobacterial pathogen. The drug is selected from Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, Streptomycin, Ciprofloxacin, Moxifloxacin, Ofloxacin, Amikacin, Capreomycin, Kanamycin, Prothionamide, Ethionamide, Paraaminosalicylic acid, Cycloserine, Rifabutin and Levofloxacin, and it is intended only for use in treatment of a patient suffering from infection by a mycobacterial strain that has been determined to be susceptible to treatment by the particular drug by a method according to any one the above embodiments of the first aspect of the invention.

The invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

Wherever alternatives for single separable features are laid out herein as “embodiments”, it is to be understood that such alternatives may be combined freely to form discrete embodiments of the invention disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic overview of the method according to the first aspect of the invention.

Table 1 shows the threshold values to compare the predictor to for each of 17 antibiotics, in order to determine whether a sample is resistant or susceptible

Antibacterial drug Threshold Isoniazid −1.166 Rifampicin −0.318 Ethambutol −1.775 Pyrazinamide −3.426 Streptomycin −2.501 Ciprofloxacin −4.815 Moxifloxacin −2.547 Ofloxacin −1.774 Amikacin −4.729 Capreomycin −1.531 Kanamycin −3.033 Prothionamide −0.551 Ethionamide −2.589 Para-aminosalicylic acid −2.598 Cycloserine −1.859 Rifabutin −0.605 Levofloxacin −2.358

Tables A through Q show the weights to be added for a set of positions present or absent in the patient sample mycobacterial sequence for each of 17 antibiotics. The result of the addition over all sequences of any one of Tables A to Q is the predictor.

EXAMPLES Example 1

-   -   1. DNA is isolated from a clinical specimen or from a cultured         isolate (1A) or a clinical specimen (1B) such as sputum, blood,         urine, wounds, biopsies, etc. using standard DNA isolation         extraction protocols (1) (such as the one described in de         Almeida BMC Research Notes 2013 6:561), to yield DNA of good         quality,     -   2. The DNA is fragmented mechanically or enzymatically in the         case of whole genome sequencing     -   3. OR the DNA is amplified in a multiplex PCR reaction with         appropriate conditions, for targeted locus amplification, using         a PCR primer panel covering within its amplicons mutations found         in Tables A-Z,     -   4. The amplicons are thereafter converted to libraries suitable         for sequencing using an NGS platform (either from Illumina,         Iontorrent or Oxford nanopore) using manufacturer recommendation         of the NGS platform to be used. This does not exclude other and         future platforms.     -   5. The libraries are quality checked using capillary based         electrophoresis systems (such as Fragment Analyzer (AATI) or         QIAxcel Advanced or other, to determine the size distribution of         the libraries.     -   6. The libraries are quantified using an appropriate         fluorometric method (such as Qubit or Quantus or other) or         equalized using a library equalizer kit.     -   7. The libraries are pooled and diluted to appropriate amounts         as recommended by the NGS system which they are going to be         sequenced on.     -   8. The libraries are sequenced as per manufacturers'         recommendation to achieve adequate read length and depth.     -   9. The sequencing reads are de-multiplexed and acquired in         appropriate formats (e.g. FastQ format) by the software         delivered with the NGS instrument or other third-party software.     -   10. The FastQ sequencing reads are aligned to the reference         genome of M. tuberculosis (Genbank accession NC_000962.3) using         a short read aligner such as bwa [Li H. (2013) Aligning sequence         reads, clone sequences and assembly contigs with BWA-MEM.         arXiv:1303.3997v29], SOAP aligner [“SOAP2: an improved ultrafast         tool for short read alignment” (2009) BIOINFORMATICS,         doi:10.1093/bioinformatics/btp336], stampy [Lunter, G.;         Goodson, M. (2011). “Stampy: A statistical algorithm for         sensitive and fast mapping of Illumina sequence reads”. Genome         Research 21 (6): 936-939. doi:10.1101/gr.111120.1109 or         equivalent. The resulting alignment is used to call mutations,         e.g. statistical deviations from the reference sequence. This is         achieved using software such as SAMtool pileup [Li H, A         statistical framework for SNP calling, mutation discovery,         association mapping and population genetical parameter         estimation from sequencing data, Bioinformatics (2011) 27(21)         2987-939, freebayes [http://arxiv.org/abs/1207.39079] or VarDict         [Zhongwu Lai, Aleksandra Markovets, Miika Ahdesmaki, Brad         Chapman, Oliver Hofmann, Robert McEwen, Justin Johnson, Brian         Dougherty, J. Carl Barrett, Jonathan R. Dry; VarDict: a novel         and versatile variant caller for next-generation sequencing in         cancer research, Nucleic Acids Research, Volume 44, Issue 11, 20         Jun. 2016, Pages e108, https://doi.org/10.1093/nar/gkw227]. This         set of mutations forms the basis for the present invention. For         each mutation found in the sample that is also present in any         Table A-Z, the weight from the respective table is added         together with all other mutations found in the same table. This         sum is then compared to the threshold from Table 2 for the         respective antibiotic (see Figure). If the sum is smaller or         equal to the threshold, the sample is called ‘resistant’ in any         other case it is call ‘susceptible’. This procedure is repeated         for each antibiotic of interest, yielding an antibiogram.     -   11. The antibiogram from the previous step along with other         potentially interesting information and quality control metrics         (e.g. coverage depth and uniformity) is put into a report to be         shown, judged and analyzed by the treating physician, which may         act on this information to choose an appropriate antibiotic         therapy for the patient.

Example 2

Applying the method of as described in this specification to 5870 sequenced Tb isolates (which can be downloaded from public databases using the following accession list) yields the performance shown in FIG. 2. The sequence data was downloaded from public databases, aligned against the genome of M. tuberculosis (Genbank accession NC_000962.3) and all mutations extracted as described in Step 10 of the example Embodiment, using information from Tables A, B, C and D.

Accuracy, Sensitivity and Specificity were calculated based on the results of phenotypic drug susceptibility testing as published in (The CRyPTIC Consortium et al., N ENGL J MED (2018) 379; 15). These results were obtained with use of an MGIT 960 system (Becton Dickinson), by culture on 7H10 or Löwenstein-Jensen agar or by microscopic-observation drug-susceptibility assay. The published results are considered the phenotypic reference method. Accuracy is the fraction of cases that was predicted correctly (i.e. the phenotypic reference result was predicted). Sensitivity is the proportion of correct predictions from the total of cases that were predicted “R” (i.e. resistant) by the phenotypic reference method. Sensitivity is the fraction of cases that were correctly predicted “S” (i.e. sensitive) from the total number of cases predicted as “S” by the reference method.

Sequence accession numbers for this example:

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ERR2510521, ERR2510520, ERR2510883, ERR2510358, ERR2510259, ERR2510359, ERR2510697, ERR2510631, ERR2510409, ERR2510325, ERR2510295, ERR2510497, ERR2510404, ERR2510602, ERR2510371, ERR2510441, ERR2510608, ERR2510266, ERR2510303, ERR2510246, ERR2510354, ERR2510484, ERR2510274, ERR2510467, ERR2510575, ERR2510418, ERR2510611, ERR2510382, ERR2510375, ERR2510424, ERR2510870, ERR2510568, ERR2510430, ERR2510486, ERR2510554, ERR2510376, ERR2510363, ERR2510475, ERR2510626, ERR2510505, ERR2510439, ERR2510311, ERR2510377, ERR2510252, ERR2510542, ERR2510253, ERR2510415, ERR2510860, ERR2510633, ERR2510381, ERR2510422, ERR2510543, ERR2510333, ERR2510280, ERR2510508, ERR2510410, ERR2510547, ERR2510570, ERR2510338, ERR2510569, ERR2510698, ERR2510649, ERR2510392, ERR2510515, ERR2510582, ERR2510444, ERR2510478, ERR2510451, ERR2510446, ERR2510517, ERR2510606, ERR2510309, ERR2510643, ERR2510544, ERR2510518, ERR2510315, ERR2510335, ERR2510362, ERR2510640, ERR2510425, ERR2510541, ERR2510305, ERR2510489, ERR2510539, ERR2510579, ERR2510516, ERR2510503, ERR2510438, ERR2510466, ERR2510284, ERR2510411, ERR2510302, ERR2510511, ERR2510291, ERR2510368, ERR2510394, ERR2510591, ERR2510298, ERR2510621, ERR2510500, ERR2510339, ERR2510652, ERR2510258, ERR2510550, ERR2510562, ERR2510556, ERR2510433, ERR2510417, ERR2510401, ERR2510533, ERR2510426, ERR2510351, ERR2510490, ERR2510379, ERR2510372, ERR2510618, ERR2510536, ERR2510620, ERR2510334, ERR2510617, ERR2510347, ERR2510365, ERR2510312, ERR2510531, ERR2510449, ERR2510245, ERR2510504, ERR2510645, ERR2510560, ERR2510551, ERR2510324, ERR2510595, ERR2510356, ERR2510465, ERR2510491, ERR2510361, ERR2510349, ERR2510261, ERR2510297, ERR2510260, ERR2510609, ERR2510509, ERR2510355, ERR2510282, ERR2510623, ERR2510321, ERR2510272, ERR2510629, ERR2510607, ERR2510488, ERR2041785, ERR2041771, ERR2200148, ERR2041688, ERR2041773, ERR2041780, ERR2041741, ERR2041696, ERR2041734, ERR2041709, ERR2041786, ERR2041746, ERR2041727, ERR2041788, ERR2041753, ERR2041783, ERR2041782, ERR2041758, ERR2041744, ERR2041742, ERR2041706, ERR2041794, ERR2041793, ERR2041683, ERR2041721, ERR2041760, ERR2041767, ERR2041689, ERR2041770, ERR2041756, ERR2041804, ERR2041764, ERR2041752, ERR2041723, ERR2041805, ERR2041761, ERR2041803, ERR2200092, ERR2041684, ERR2041714, ERR2041732, ERR2041733, ERR2041766, ERR2041777, ERR2041775, ERR2041708, ERR2041718, ERR2041736, ERR2041762, ERR2041685, ERR2041776, ERR2041757, ERR2041795, ERR2041730, ERR2041747, ERR2041719, ERR2041774, ERR2041739, ERR2041789, ERR2041729, ERR2041716, ERR2041749, ERR2041702, ERR2041700, ERR2041738, ERR2041765, ERR2041745, ERR2041735, ERR2199914, ERR2041693, ERR2041769, ERR2041800, ERR2041711, ERR2041731, ERR2041791, ERR2041768, ERR2041750, ERR2041772, ERR2041759, ERR2041798, ERR2041751, ERR2041787, ERR2041802, ERR2041712, ERR2041704, ERR2041717, ERR2200070, ERR2041720, ERR2041781, ERR2041796, ERR2041682, ERR2200093, ERR2041722, ERR2041698, ERR2041754, ERR2041784, ERR2041763, ERR2041743, ERR2041748, ERR2041724, ERR2041728, ERR2041755, ERR2515105, ERR2515106, ERR2515107, ERR2515108, ERR2515109, ERR2515110, ERR2515111, ERR2515112, ERR2515113, ERR2515114, ERR2515116, ERR2515117, ERR2515118, ERR2515119, ERR2515120, ERR2515121, ERR2515122, ERR2515123, ERR2515124, ERR2515125, ERR2515126, ERR2515127, ERR2515128, ERR2515129, ERR2515130, ERR2515131, ERR2515132, ERR2515134, ERR2515136, ERR2515137, ERR2515138, ERR2515139, ERR2515140, ERR2515141, ERR2515143, ERR2515145, ERR2515146, ERR2515147, ERR2515148, ERR2515149, ERR2515150, ERR2515151, ERR2515154, ERR2515155, ERR2515156, ERR2515157, ERR2515158, ERR2515160, ERR2515161, ERR2515162, ERR2515163, ERR2515164, ERR2515166, ERR2515167, ERR2515168, ERR2515169, ERR2515170, ERR2515171, ERR2515172, ERR2515174, ERR2515176, ERR2515177, ERR2515178, ERR2515179, ERR2515180, ERR2515181, ERR2515182, ERR2515183, ERR2515184, ERR2515185, ERR2515186, ERR2515187, ERR2515188, ERR2515189, ERR2515190, ERR2515192, ERR2515193, ERR2515194, ERR2515195, ERR2515196, ERR2515197, ERR2515198, ERR2515200, ERR2515201, ERR2515202, ERR2515203, ERR2515204, ERR2515205, ERR2515206, ERR2515207, ERR2515208, ERR2515209, ERR2515210, ERR2515211, ERR2515212, ERR2515214, ERR2515215, ERR2515216, ERR2515217, ERR2515218, ERR2515219, ERR2515220, ERR2515221, ERR2515222, ERR2515224, ERR2515225, ERR2515226, ERR2515227, ERR2515228, ERR2515229, ERR2515230, ERR2515231, ERR2515232, ERR2515233, ERR2515234, ERR2515235, ERR2515236, ERR2515237, ERR2515239, ERR2515240, ERR2515241, ERR2515242, ERR2515243, ERR2515244, ERR2515245, ERR2515246, ERR2515247, ERR2515249, ERR2515251, ERR2515252, ERR2515253, ERR2515254, ERR2515255, ERR2515256, ERR2515257, ERR2515258, ERR2515259, ERR2515260, ERR2515261, ERR2515262, ERR2515264, ERR2515265, ERR2515266, ERR2515267, ERR2515268, ERR2515269, ERR2515270, ERR2515272, ERR2515273, ERR2515274, ERR2515275, ERR2515276, ERR2515277, ERR2515278, ERR2515279, ERR2515280, ERR2515281, ERR2515282, ERR2515283, ERR2515284, ERR2515285, ERR2515287, ERR2515288, ERR2515289, ERR2515290, ERR2515291, ERR2515292, ERR2515293, ERR2515294, ERR2515295, ERR2515297, ERR2515298, ERR2515299, ERR2515300, ERR2515301, ERR2515302, ERR2515303, ERR2515304, ERR2515305, ERR2515306, ERR2515307, ERR2515308, ERR2515309, ERR2515310, ERR2515311, ERR2515312, ERR2515313, ERR2515314, ERR2515315, ERR2515316, ERR2515317, ERR2515318, ERR2515320, ERR2515321, ERR2515323, ERR2515324, ERR2515326, ERR2515327, ERR2515328, ERR2515329, ERR2515330, ERR2515332, ERR2515334, ERR2515336, ERR2515338, ERR2515339, ERR2515340, ERR2515341, ERR2515342, ERR2515343, ERR2515345, ERR2515346, ERR2515347, ERR2515348, ERR2515349, ERR2515350, ERR2515351, ERR2515352, ERR2515353, ERR2515355, ERR2515356, ERR2515357, ERR2515359, ERR2515360, ERR2515362, ERR2515363, ERR2515364, ERR2515365, ERR2515366, ERR2515367, ERR2515368, ERR2515369, ERR2515370, ERR2515371, ERR2515372, ERR2515374, ERR2515375, ERR2515376, ERR2515377, ERR2515378, ERR2515379, ERR2515380, ERR2515381, ERR2515382, ERR2515383, ERR2515384, ERR2515385, ERR2515387, ERR2515388, ERR2515389, ERR2515390, ERR2515391, ERR2515392, ERR2515393, ERR2515394, ERR2515395, ERR2515396, ERR2515397, ERR2515398, ERR2515399, ERR2515400, ERR2515401, ERR2515402, ERR2515403, ERR2515404, ERR2515406, ERR2515407, ERR2515408, ERR2515409, ERR2515410, ERR2515412, ERR2515413, ERR2515414, ERR2515416, ERR2515417, ERR2515418, ERR2515420, ERR2515421, ERR2515422, ERR2515423, ERR2515424, ERR2515426, ERR2515428, ERR2515429, ERR2515431, ERR2515432, ERR2515433, ERR2515434, ERR2515435, ERR2515436, ERR2515437, ERR2515438, ERR2515439, ERR2515440, ERR2515441, ERR2515442, ERR2515443, ERR2515444, ERR2515445, ERR2515446, ERR2515447, ERR2515448, ERR2515449, ERR2515450, ERR2515451, ERR2515452, ERR2515453, ERR2515454, ERR2515455, ERR2515456, ERR2515457, ERR2515459, ERR2515460, ERR2515461, ERR2515462, ERR2515463, ERR2515464, ERR2515465, ERR2515466, ERR2515467, ERR2515468, ERR2515469, ERR2515470, ERR2515471, ERR2515472, ERR2515474, ERR2515476, ERR2515477, ERR2515478, ERR2515480, ERR2515481, ERR2515482, ERR2515483, ERR2515484, ERR2515485, ERR2515486, ERR2515487, ERR2515488, ERR2515489, ERR2515490, ERR2515491, ERR2515492, ERR2515493, ERR2515494, ERR2515495, ERR2515496, ERR2515497, ERR2515498, ERR2515499, ERR2515500, ERR2515501, ERR2515502, ERR2515503, ERR2515504, ERR2515505, ERR2515506, ERR2515515, ERR2515516, ERR2515517, ERR2515518, ERR2515521, ERR2515522, ERR2515523, ERR2515524, ERR2515525, ERR2515526, ERR2515527, ERR2515529, ERR2515530, ERR2515531, ERR2515532, ERR2515533, ERR2515534, ERR2515535, ERR2515536, ERR2515537, ERR2515538, ERR2515539, ERR2515540, ERR2515542, ERR2515543, ERR2515545, ERR2515547, ERR2515548, ERR2515549, ERR2515550, ERR2515551, ERR2515552, ERR2515553, ERR2515554, ERR2515555, ERR2515556, ERR2515557, ERR2515558, ERR2515559, ERR2515561, ERR2515562, ERR2515563, ERR2515564, ERR2515565, ERR2515566, ERR2515567, ERR2515569, ERR2515570, ERR2515571, ERR2515572, ERR2515573, ERR2515574, ERR2515576, ERR2515577, ERR2515578, ERR2515579, ERR2515580, ERR2515581, ERR2515582, ERR2515585, ERR2515586, ERR2515587, ERR2515592, ERR2515593, ERR2515595, ERR2515596, ERR2515598, ERR2515599, ERR2515600, ERR2515601, ERR2515602, ERR2515603, ERR2515604, ERR2515605, ERR2515606, ERR2515607, ERR2515608, ERR2515610, ERR2515611, ERR2515612, ERR2515613, ERR2515614, ERR2515615, ERR2515616, ERR2515617, ERR2515618, ERR2515619, ERR2515620, ERR2515622, ERR2515623, ERR2515624, ERR2515625, ERR2515626, ERR2515627, ERR2515628, ERR2515629, ERR2515630, ERR2515631, ERR2515632, ERR2515633, ERR2515634, ERR2515635, ERR2515637, ERR2515638, ERR2515639, ERR2515642, ERR2515643, ERR2515644, ERR2515645, ERR2515646, ERR2515648, ERR2515649, ERR2515651, ERR2515652, ERR2515653, ERR2515654, ERR2515655, ERR2515656, ERR2515657, ERR2515659, ERR2515661, ERR2515662, ERR2515663, ERR2515664, ERR2515665, ERR2515666, ERR2515668, ERR2515670, ERR2515671, ERR2515672, ERR2515673, ERR2515674, ERR2515675, ERR2515676, ERR2515677, ERR2515678, ERR2515679, ERR2515680, ERR2515681, ERR2515682, ERR2515683, ERR2515684, ERR2515685, ERR2515686, ERR2515687, ERR2515688, ERR2515689, ERR2515690, ERR2515691, ERR2515692, ERR2515693, ERR2515694, ERR2515695, ERR2515696, ERR2515697, ERR2515698, ERR2515699, ERR2515700, ERR2515701, ERR2515702, ERR2515703, ERR2515705, ERR2515706, ERR2515707, ERR2515709, ERR2515711, ERR2515712, ERR2515713, ERR2515714, ERR2515715, ERR2515716, ERR2515717, ERR2515718, ERR2515720, ERR2515721, ERR2515722, ERR2515723, ERR2515724, ERR2515726, ERR2515727, ERR2515728, ERR2515729, ERR2515730, ERR2515731, ERR2515733, ERR2515734, ERR2515735, ERR2515736, ERR2515737, ERR2515738, ERR2515740, ERR2515741, ERR2515742, ERR2515744, ERR2515745, ERR2515748, ERR2515749, ERR2515750, ERR2515751, ERR2515752, ERR2515753, ERR2515755, ERR2515757, ERR2515758, ERR2515759, ERR2515760, ERR2515761, ERR2515762, ERR2515763, ERR2515764, ERR2515765, ERR2515766, ERR2515767, ERR2515769, ERR2515770, ERR2515771, ERR2515772, ERR2515773, ERR2515774, ERR2515775, ERR2515777, ERR2515778, ERR2515779, ERR2515780, ERR2515781, ERR2515782, ERR2515783, ERR2515784, ERR2515785, ERR2515786, ERR2515787, ERR2515788, ERR2515790, ERR2515791, ERR2515792, ERR2515793, ERR2515795, ERR2515796, ERR2515798, ERR2515799, ERR2515800, ERR2515801, ERR2515803, ERR2515804, ERR2515805, ERR2515807, ERR2515808, ERR2515809, ERR2515811, ERR2515813, ERR2515814, ERR2515815, ERR2515816, ERR2515817, ERR2515818, ERR2515819, ERR2515820, ERR2515821, ERR2515822, ERR2515823, ERR2515824, ERR2515825, ERR2515827, ERR2515828, ERR2515829, ERR2515830, ERR2515831, ERR2515832, ERR2515836, ERR2515838, ERR2515840, ERR2515841, ERR2515842, ERR2515843, ERR2515844, ERR2515845, ERR2515846, ERR2515847, ERR2515848, ERR2515849, ERR2515850, ERR2515851, ERR2515852, ERR2515853, ERR2515854, ERR2515855, ERR2515856, ERR2515857, ERR2515858, ERR2515859, ERR2515861, ERR2515862, ERR2515863, ERR2515865, ERR2515866, ERR2515868, ERR2515869, ERR2515870, ERR2515871, ERR2515873, ERR2515874, ERR2515875, ERR2515876, ERR2515877, ERR2515879, ERR2515880, ERR2515881, ERR2515882, ERR2515883, ERR2515884, ERR2515885, ERR2515886, ERR2515887, ERR2515888, ERR2515889, ERR2515890, ERR2515891, ERR2515892, ERR2515893, ERR2515894, ERR2515895, ERR2515896, ERR2515897, ERR2515899, ERR2515900, ERR2515901, ERR2515902, ERR2515903, ERR2515904, ERR2515905, ERR2515906, ERR2515907, ERR2515908, ERR2515909, ERR2515912, ERR2515913, ERR2515914, ERR2515915, ERR2515916, ERR2515917, ERR2515919, ERR2515921, ERR2515922, ERR2515923, ERR2515925, ERR2515927, ERR2515928, ERR2515929, ERR2515930, ERR2515932, ERR2515933, ERR2515934, ERR2515935, ERR2515936, ERR2515937, ERR2515938, ERR2515939, ERR2515940, ERR2515941, ERR2515942, ERR2515944, ERR2515945, ERR2515946, ERR2515947, ERR2515948, ERR2515949, ERR2515950, ERR2515951, ERR2515952, ERR2515953, ERR2515954, ERR2515955, ERR2515956, ERR2515957, ERR2515958, ERR2515959, ERR2515960, ERR2515961, ERR2515962, ERR2515963, ERR2515964, ERR2515966, ERR2515967, ERR2515968, ERR2515969, ERR2515970, ERR2515972, ERR2515973, ERR2515974, ERR2515975, ERR2515976, ERR2515977, ERR2515978, ERR2515979, ERR2515980, ERR2515981, ERR2515982, ERR2515983, ERR2515984, ERR2515985, ERR2515986, ERR2515987, ERR2515989, ERR2515991, ERR2515992, ERR2515993, ERR2515994, ERR2515995, ERR2515997, ERR2515998, ERR2515999, ERR2516000, ERR2516001, ERR2516002, ERR2516003, ERR2516004, ERR2516006, ERR2516007, ERR2516008, ERR2516009, ERR2516010, ERR2516011, ERR2516013, ERR2516015, ERR2516016, ERR2516020, ERR2516021, ERR2516022, ERR2516024, ERR2516025, ERR2516026, ERR2516027, ERR2516028, ERR2516029, ERR2516030, ERR2516031, ERR2516032, ERR2516033, ERR2516034, ERR2516035, ERR2516036, ERR2516037, ERR2516038, ERR2516039, ERR2516040, ERR2516042, ERR2516043, ERR2516044, ERR2516046, ERR2516047, ERR2516048, ERR2516050, ERR2516051, ERR2516052, ERR2516053, ERR2516054, ERR2516056, ERR2516057, ERR2516058, ERR2516060, ERR2516061, ERR2516062, ERR2516065, ERR2516067, ERR2516069, ERR2516070, ERR2516071, ERR2516072, ERR2516073, ERR2516074, ERR2516075, ERR2516076, ERR2516078, ERR2516080, ERR2516081, ERR2516082, ERR2516083, ERR2516084, ERR2516085, ERR2516086, ERR2516087, ERR2516088, ERR2516089, ERR2516090, ERR2516091, ERR2516092, ERR2516093, ERR2516094, ERR2516095, ERR2516096, ERR2516097, ERR2516098, ERR2516099, ERR2516100, ERR2516101, ERR2516102, ERR2516103, ERR2516104, ERR2516105, ERR2516106, ERR2516107, ERR2516108, ERR2516109, ERR2516110, ERR2516111, ERR2516112, ERR2516113, ERR2516114, ERR2516115, ERR2516116, ERR2516117, ERR2516118, ERR2516119, ERR2516121, ERR2516122, ERR2516123, ERR2516124, ERR2516125, ERR2516126, ERR2516127, ERR2516128, ERR2516129, ERR2516130, ERR2516131, ERR2516132, ERR2516133, ERR2516134, ERR2516135, ERR2516136, ERR2516137, ERR2516138, ERR2516139, ERR2516140, ERR2516142, ERR2516143, ERR2516144, ERR2516145, ERR2516147, ERR2516148, ERR2516149, ERR2516150, ERR2516151, ERR2516152, ERR2516153, ERR2516154, ERR2516155, ERR2516156, ERR2516157, ERR2516158, ERR2516159, ERR2516160, ERR2516161, ERR2516162, ERR2516163, ERR2516164, ERR2516165, SRR6369878, SRR6369877, SRR6369876, SRR6369875, SRR6367401, SRR6367400, SRR6367399, SRR6367398, SRR6367396, SRR6339667, SRR6339666, SRR6339665, SRR6339664, SRR6339662, SRR6339661, SRR6339653, SRR6339651, SRR6339649, SRR6339648, SRR6339645, SRR6339644, SRR6339643, SRR6339642, SRR6339641, SRR6339640, SRR6339637, SRR5817481, SRR5817480, SRR5817479, SRR5817478, SRR5817475, SRR5817473, SRR5817472, SRR5817471, SRR5817470, SRR5817469, SRR5817467, SRR5817466, SRR5817464, SRR5817463, SRR2333215, SRR2328057

TABLE A Isoniazid weighted positions; threshold value: -1.166 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC -1.611 2155541 A G -0.4418 4327448 A C -2.066 1083962 C A -3.895 2155546 T C -1.924 4328019 C T -0.632 1137943 C T -1.732 2155546 T G -1.232 4328037 G A -2.47 1237557 A C -1.611 2155563 G T -0.6722 4328059 C A -3.895 1237609 C A -3.895 2155607 C T -2.233 4399252 AGC GGG -0.599 1416409 C G -3.347 2155624 T G -3.624 4400008 G A -3.895 1416432 C T -3.236 2155636 A G -3.576 4403518 T C -0.1727 1417140 C T -0.018 2155648 T C -2.761 4407583 C T -2.591 1472041 C T -4.128 2155687 T C -0.4141 4407731 GCC GC -1.326 1472069 G T -1.611 2155689 C G -2.727 4407793 C T -4.128 1472127 CGG TGCTCT -3.895 2155738 C T -3.784 4407824 G A -3.895 1472359 A C -0.223 2155740 GCCCCC GCCCC -2.319 4407846 GGCGC GGCGC -3.895 G G GCC C 1472362 C T -0.046 2155786 G A -3.624 4407896 C A -0.08956 1472428 G T -3.443 2155787 C T -2.382 4407913 C T -0.7143 1472487 CTA CTTA -4.154 2155801 C T -2.062 4407927 T G -0.06442 1472753 A T -3.502 2155817 C T -2.81 4407976 C T -1.889 1472772 C T -3.895 2155844 A G -2.327 4407979 G C -0.7918 1472866 C T -3.826 2155959 GTT GT -0.1331 4407985 C G -0.4042 1473246 A G -0.881 2156066 C G -3.856 4407994 C T -3.56 1473254 A C -0.745 2223293 T C  3.263 4408006 A G -3.895 1473260 G T -2.098 2223757 G A -1.037 4408066 TCC TC -3.895 1473959 TTGT GTGG -1.233 2279395 C T -1.982 4408100 GCCCCC GCCCC -0.7235 G G 1474313 T C -3.895 2279868 GCCT GCCCCT -3.895 4408102 C A  0.7047 1474686 A G -2.403 2288730 G T  3.732 4408159 C G -1.839 1475116 G T -0.218 2288932 TGTACG TG -2.647 496582 C T -3.895 1475751 C T -3.850 2289214 G A -1.81 497248 T G -0.7344 1476442 T C -4.387 2412005 A C -0.7962 510741 C A -2.349 1490779 C T -4.128 2518871 C T -3.78 511087 A C -3.253 1491719 C T -0.767 2694045 C G -0.1311 511319 G T  1.864 1501288 C T -3.715 2694909 G A  0.6835 513282 G A -1.611 1501977 A C -0.644 2714465 G T -1.611 514180 C G -1.338 157174 T C -0.251 2714929 G T -1.035 514876 G C  0.3029 1673425 C T -2.339 2715215 C T -2.332 515110 T G  0.2691 1674048 G A -0.183 2726136 C T  1.164 538698 A C -3.895 1674248 T C -1.759 2726146 GA GTA  0.2011 540078 C G -2.858 1674262 A G -2.415 2726480 G T -4.128 5413 G A -0.02688 1674263 T C -3.551 2726775 G A -3.895 5416 C T -1.902 1674481 T G -0.950 273788 G T -2.167 5440 A C  2.137 1674769 G T -2.135 2751831 G T -4.128 5446 G T -1.765 1674772 G A -2.030 2751934 GGA GGC -2.519 5548 A G -1.823 1674782 T C -2.877 2752122 G C -0.04813 5548 A C -1.759 1718818 G C -3.895 2937452 C T -3.895 5597 C T -4.128 1758093 C G -0.248 2939373 G C  0.2417 575544 G T  0.5595 1833555 C G -1.869 2939510 C G -0.9458 575608 G A  2.37 1833594 C A  0.111 2939609 C A -3.895 575797 C T -3.994 1833906 A T -3.912 2939758 C T -3.895 576316 A G -2.08 1834177 A C -0.103 2940759 CCCG CCCC  0.2827 576472 C A -2.287 1834279 C T -3.994 2955150 G A -0.2147 576526 C T -2.935 1834540 G T -0.320 2956140 A G -0.8646 576660 T G -1.611 1849536 C T -3.895 2956571 G C -1.611 576693 A C -0.609 1850296 G A -1.228 3074361 A G -3.895 576751 G C -0.1557 1851131 T G -1.469 3272239 T G -0.1907 5849 C A -1.528 1851384 C A  0.101 3296300 C A  1.352 5980 G C -4.128 1875470 T G -3.624 3296919 T C -0.1295 6016 C G -0.8755 1875502 GTT GT -3.376 3296962 G C -3.624 61178 C T -3.895 1875567 G C -2.737 3296992 G C -2.22 614975 G C -0.1391 1875600 C T -0.498 3297120 CGG CG  3.406 61988 C T -3.895 1875709 T G -0.539 3297442 CAT CAAT  0.7593 62196 G A -1.551 1875902 T C -0.900 3326394 A G -3.895 6302 G T -2.822 1876608 C G -0.745 3388356 A C -3.754 6358 C T  0.3993 1877312 G T -3.290 3465908 G C -1.077 6794 A G -3.994 1877638 A G -0.799 347401 C G -3.895 7170 C A -2.705 1877670 C T  0.184 347449 C G -1.611 7200 A C -2.215 1877727 C T  1.105 3479610 T C -3.715 7246 T A -3.895 1877909 TGGGCC GGGGG  0.984 3479632 G A -2.369 7361 CG TC  0.393 GGT CGGG 1878049 G T -2.519 348178 C T -3.631 7362 G C  2.081 1878163 C G -3.624 348662 C A  3.1 7570 C T -0.2999 1878591 G T -3.624 355725 G C -2.087 7570 C G -0.4919 1879244 TGGT GGGG -0.280 3570160 A G -0.6069 760011 G C -4.259 1879316 C T -1.753 3570229 C G -4.088 760306 G A -0.7102 1879517 G T -3.895 3987048 G A -1.247 760309 T C -3.281 1879632 C A -3.715 403565 T G  0.2367 760314 G T -0.0489 1879654 T G -3.416 403634 G T -2.605 760912 A C -2.814 1880070 A C  0.297 404356 T G  5.312 760978 A G -1.879 1880381 G T -3.718 405812 T C -2.158 761074 A G -0.1354 1880632 G A -3.895 4124826 A C -0.2273 761076 T G -2.026 1881378 CGG CG -0.831 4124832 T C -1.77 761093 G T -0.6438 1883766 TGA GGG -0.854 4124884 T G -0.4097 761093 G C -0.1684 1883801 C T -3.135 4238385 G A  0.3323 761095 T C -0.3701 1886422 T G -0.610 4240562 A C -2.672 761098 GCCAA GCCACC -4.049 AA 1886509 T G -1.270 4241758 G A -3.58 761100 CAATTC CA -1.161 ATGGA (SEQ ID NO 001) 2053666 T G -1.399 4242704 G A -4.619 761109 G T -1.79 2101853 A G -0.959 4243323 G A -0.3996 761110 A T -0.9756 2101915 A G -0.048 4243430 G A -3.121 761115 A C -0.6562 2102207 C T -1.120 4243730 G C -3.739 761131 G A -1.707 2102521 G A -3.895 4243803 A G -4.128 761135 GACCCA TACCTG -3.282 2102615 T G -3.895 4243830 G A -1.421 761139 C T -0.7426 2102638 T C -3.807 4244069 C T  0.7047 761139 C G -0.6112 2102778 C A -1.759 4244093 C T -3.895 761139 CA GG -3.895 2153813 A C  0.268 4244286 G A -3.994 761139 CA AG -5.132 2154016 C A -0.425 4244474 G A -3.895 761140 A T -0.1099 2154108 C T -3.895 4244631 A C -0.1459 761154 TCGGC CAGGG -2.088 2154211 AGG AGGG -2.562 4244815 T G -3.624 761155 C G -1.437 2154232 A G -2.864 4245187 C A -0.06857 761155 C T -1.897 2154240 C T -0.963 4245226 A G -2.581 761161 T C -0.3494 2154332 A T -0.133 4245311 C G -2.368 761729 C T -1.759 2154354 CAC CC -2.030 4246759 C G -4.564 761828 C G -0.7551 2154461 CG CTG -2.695 4246791 C T -2.22 761889 G C -4.506 2154590 T C -0.239 4247050 C T -0.6455 762072 A G -2.03 2154746 CAA CA -3.814 4247429 A G -0.7152 762399 G T -3.404 2154761 CGACGA CG -3.314 4247431 G A -0.3476 762974 G C -2.011 GGTCGT GG (SEQ ID NO 002) 2154823 AG GC -3.624 4247573 G A -0.6191 763039 C T -0.8927 2154834 G C -3.416 4247574 A G -2.04 763111 A C -2.545 2154877 C T -4.619 4247729 G A -0.947 764992 G A -4.249 2154973 G T -2.030 4248184 G C  3.302 766047 C T -3.856 2154973 G A -1.565 4248200 A C -0.02467 766767 A C -0.384 2155102 T C  0.271 4248343 G A -2.03 7776 C G -0.6437 2155120 C A -2.664 4248516 T C -3.895 779316 G T -1.611 2155167 GC TG -3.292 4249323 C A -0.211 781687 A G -0.7727 2155167 GC AG -3.141 4249327 G A -2.964 781822 A G -0.5346 2155167 GC CG -2.978 4249545 A C -3.895 781822 A T -0.6246 2155168 C G -5.426 4249746 T G  2.37 7862 C T -0.08349 2155168 C T -4.725 4258251 A G -0.3831 8017 G A -3.735 2155168 C A -4.005 4258832 G A -1.714 8171 G T  2.137 2155168 CTGGT GTGGC -0.677 4259665 G C -2.03 8303 C T -3.895 2155169 T C -3.082 4260684 C A -4.025 8393 T C -2.87 2155206 G C -2.961 4269317 A C -0.4345 8668 C G -4.128 2155212 C G -3.580 4308395 G A -0.05994 8717 C G -1.259 2155213 C G -1.068 4326101 T C -3.624 875532 C G -1.611 2155217 C T -2.780 4326282 C A -1.611 891663 T C -3.895 2155300 G A -2.029 4326313 G A -3.895 891865 A C -3.289 2155351 C A -3.895 4326737 T C -0.9851 892128 C T -2.928 2155416 CG CAG -3.494 4326800 A G -0.667 9276 C T -2.848 2155418 G A  0.230 4326980 T G -2.604 9392 C T -4.727 2155430 T G -1.552 4327133 T G -2.713 9437 G A -4.128 2155478 CG CAG -3.624 4327323 G A -1.266 9719 G C -3.725 9735 C T -3.895

TABLE B Rifampicin weighted positions; threshold value: -0.318 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC -1.079 2751953 C AG  0.2904 5452 G A -1.116 1084659 T G  2.688 2751960 A G  0.0804 575760 G T -3.147 1085605 C T -1.079 2752074 T G -0.3468 576618 ACGC ACGCG -0.5844 C 1128074 A G -0.190 2752122 G C -0.04697 576660 T G -1.079 1131738 T C -3.434 2831532 G T  2.254 576710 C G -0.1681 1132004 A C -3.294 2875149 T G  0.4523 61178 C T -2.25 1237557 A C -1.079 2876064 T C -0.07538 615211 T G  0.05838 1472069 G T -1.079 2939020 A T  1.899 616092 G T -1.559 1472155 C A -0.918 2939609 C A -4.82 616196 A C -2.11 1472359 A C -0.070 2956293 ACTGC AC  0.1812 61988 C T -3.148 1472362 C T -0.281 2956379 C T -1.773 6302 G T -0.1179 1472674 T C -2.962 2956571 G C -1.079 6346 C T  6.218 1473246 A G -1.005 3074424 C A -0.2901 6576 G A  2.157 1474686 A G -0.270 3272997 A G -0.1621 6579 C A -1.369 1474833 G T -2.733 3273214 C A -0.6575 6794 A G -5.12 1474900 G T -0.255 3296271 T C -3.054 6866 C T  2.236 1475751 C T -1.596 3296736 T G -0.3921 7335 C T -1.429 1488086 C G  0.730 3296843 A G  1.632 7362 G C  2.091 1502745 A G -2.514 3296925 G C -0.04796 7495 GCC GCCC -3.038 1674026 A C  5.568 3296928 CCACCG CC -2.962 7521 G T -2.164 CCAGC (SEQ ID NO 003) 1674481 T G -0.792 3388838 G A  3.358 7570 C T -0.3307 1674709 T C -0.656 345504 A C -3.172 7570 C G -0.2374 1674769 G T  1.091 346563 C T -2.233 7585 G C  0.1589 1674782 T C -0.104 3466825 G C  0.825 760306 G A -0.52 1674966 T G  0.110 3467118 T C -1.273 760308 G A -0.3262 1759252 G T -0.251 347221 G C -1.208 760314 G T -4.974 1816240 G T  0.452 347393 C T -3.513 760483 A G -1.522 1816487 G T -0.499 347449 C G -1.079 761095 T C -4.684 1817357 T G -2.585 348413 C T  4.728 761095 TGA CGG -1.903 1833906 A T -1.545 348662 C A  2.599 761095 T G -0.07896 1834177 A C -0.178 349054 C T -1.716 761098 GCCAA GCCACC -4.625 AA 1849861 G A -0.412 349071 A G -1.647 761100 C A -2.983 1850293 T A -0.107 349151 A G  2.364 761100 CAATTC CA -3.292 ATGGA (SEQ ID NO 001) 1851932 C A -0.168 349205 A C -3.172 761101 A C -4.14 1875440 A C -0.923 3514463 G A  1.787 761101 A T -4.365 1875499 G T -0.521 355692 T G  0.8223 761102 ATTCA ATTCTT -3.929 CA 1875562 G C -0.064 3569664 T C -0.04971 761104 TCATGG TC -2.545 AC 1875902 T C -1.079 3569739 C G -0.2074 761107 TGGACC TG -4.712 AG 1876420 T G  0.107 3570229 C G -0.9203 761107 TGG GGT -1.868 1876531 G A -0.558 3836358 G C  1.534 761108 GG TT -1.729 1877866 G C  3.503 403565 T G  0.034 761108 GGACC GC -4.555 1877947 G A -2.402 403828 C T -3.38 761109 G T -4.337 1878128 A G -0.405 404356 T G  4.362 761109 GA TT -3.89 1878238 T G -0.607 405404 C T -3.755 761109 GA CT -2.655 1878416 A C -0.770 405479 G A -3.034 761110 A T -4.824 1878817 CGGGG CGGGG  0.860 4125415 A G -0.7979 761110 A G -0.7976 GGC GC 1879405 G T -1.878 4229167 T C -0.02295 761127 TC CA -2.151 1879716 G T  1.328 4240678 T G -0.1713 761127 TC AT -0.2862 1879823 A C -0.214 4241292 T G  7.094 761128 C T -4.343 1880329 A C -0.104 4243217 C G  1.905 761128 C G -2.946 1882443 C T -0.062 4243379 C A -0.3618 761131 G A -0.7445 1882933 T A -0.770 4244850 C G  0.2329 761134 TGACCC GGCCC -5.407 ACAA CA (SEQ ID NO 004) 1883716 T G  0.112 4245001 T C -0.1319 761135 GACCCA TACCTG -3.767 1883736 GGT GGG -3.902 4245055 C A -0.1318 761139 C T -4.49 1883750 T G -0.215 4245226 A G  0.07515 761139 C G -4.887 1886509 T G -1.767 4245311 C G  1.016 761139 C A -3.276 1917851 C A -0.435 4247429 A G -1.17 761139 CA TG -4.249 1918019 T C  0.946 4247431 G C -0.2875 761139 CA GG -4.172 1918340 C T -1.828 4247431 G A -0.9326 761139 CA AG -5.39 2054227 T G -0.431 4247431 G T -0.28 761140 A G -4.607 2102289 C T -2.168 4247507 T C  0.4568 761140 A T -4.12 2133859 C T -3.911 4247574 A C -0.06571 761141 C A -0.7741 2153819 C G -0.926 4247729 G A -0.1473 761154 TCGGC CAGGG -3.688 2154108 C T -1.744 4247730 G C -0.3736 761154 TC CA -3.204 2154158 ACTCGG AGGCCT  2.117 4247747 T C -1.89 761155 C G -4.885 AG CG 2154214 A G -0.542 4248003 A G -0.7354 761155 C T -5.572 2154695 C A -0.846 4249272 A C -0.2619 761155 CG TT -2.277 2154834 G C -0.819 4249327 G A -4.151 761155 CG TC -2.021 2154857 C G -0.261 4258428 C G  0.03848 761161 T C -3.604 2155167 GC CG -0.190 4259573 A C  0.1593 761167 CCGGC CCGGT -2.363 GGT 2155168 C G -1.490 4269162 C A -0.6126 761277 A T -3.084 2155168 C T -1.281 4269722 C A  0.5053 761278 T C -1.915 2155258 C A  7.345 4269848 T C -3.508 761279 C G -4.764 2155430 T G -1.000 4308395 G A -0.07952 761827 A G -0.3675 2155636 A G -0.100 4308402 A G -0.8195 762399 G T -3.258 2155648 T C -0.145 4308881 C T -0.1779 764181 A G -0.7252 2155746 G A  2.527 4326282 C A -1.079 764323 G T  2.117 2155819 T C -0.087 4326341 G A  1.056 764617 C T  2.167 2279407 G A -0.459 4326426 CAAAAA CAAAAG -0.5703 764749 G A  4.861 G 2288730 G T  3.271 4326611 G C  2.636 767123 G T -0.1358 2288740 T G  4.684 4326831 G A  3.238 7685 G A  1.533 2288813 GGCCG GGCCG  1.712 4326980 T G -0.006595 778953 T C -3.254 TCTGGC TCTGGC G (SEQ GCCGTC ID NO TGGCG 005) (SEQ ID NO 006) 2288850 ACC ACCC -0.105 4327241 C T  0.9404 779181 CGGGG CGGGG -0.0104 GGA GA 2288868 A C -0.059 4327294 G T  1.008 779316 G T -1.079 2288868 A T -0.449 4328212 CGGGG CGGGGT -0.6804 781822 A G -0.162 GT 2288932 TGTACG TG -0.029 4407620 A G -0.4966 781937 C T -0.6332 2289164 CGC CC  1.935 4407677 G A -0.4789 782750 T C -2.233 2289223 C G  0.680 4407734 C T  1.419 783387 C T -4.902 2412085 A C  0.154 4407847 G T -0.4189 783783 G A -0.04834 2518919 G A -0.126 4407927 T G -0.09332 7914 C A -0.5087 2620945 G T -1.268 4407940 A G -0.6359 7960 T G  1.694 2693848 G T -1.537 4407973 A G -0.5723 796747 T G -0.7455 2693851 G T -3.415 491405 T A  0.4985 8147 C G -3.338 2693853 T G -1.972 496401 T C  1.001 8435 C G -1.273 2693952 A C  0.639 497243 G C  0.1293 8721 C G -1.224 2693966 A C -1.868 497491 G A -0.1006 875005 T G  0.07587 2714465 G T -1.079 513282 G A -1.079 875532 C G -0.8313 2714566 AGGG GGGCG  0.284 513468 T G  5.44 891648 C G  0.08224 GGG 2715072 C T -0.277 514344 G A -0.0399 891788 C G  1.412 2726338 T G  0.029 5300 G A -3.867 9276 C T -1.988 273690 C T -0.185 5311 G A -0.5311 930984 T C  0.4523 274030 C T -1.916 538916 G T  0.4523 9395 G A  0.7507 2751605 ACGCAA AC -0.266 539228 C G  0.4523 9788 C T -1.861 AAGCTC CCAAAT CCGACC GGATTT GGGAG CTTTTG CGTCTT TTCGCG GTGGTC AGCCG CGGCG GCC (SEQ ID NO 007) 2751923 A G -4.616 541439 G A -3.294 9808 C T -0.2397 9846 C G -3.254

TABLE C Ethambutol weighted positions: threshold value -1.775 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC -2.458 2289031 G T -1.399 4269848 T C -2.555 1084236 G A  0.205 2289032 CGGTG CGGTG  0.9001 4308395 G A -0.0269 GTG 1084280 A G  0.548 2289038 C A -0.657 4326113 G A -0.7514 1084792 GGT GGG  0.272 2289061 T G -1.297 4326132 TGG TG -2.611 1085605 C T -2.245 2289068 G T -0.867 4326282 C A -2.458 1128074 A G -1.507 2289068 G C -0.3289 4326341 G A  0.2513 1128601 T C  0.778 2289090 T C  0.9958 4326350 G A -0.2988 1128951 G A  3.119 2289096 T C -0.1176 4326365 T G -0.2287 1131944 T C  0.273 2289097 C T  0.6811 4326547 CTT CT -2.493 1132004 A C -4.292 2289100 T C -0.06007 4326593 C T  1.046 1237205 A C -0.435 2289144 T A -1.144 4326613 GTT GT  2.72 1237557 A C -2.458 2289156 CGG CGGG -2.471 4326621 G T  3.636 1416260 A G -0.505 2289164 CGC CC  1.01 4326801 GCT GCCT -0.04766 1461119 T G  0.693 2289193 C T  1.17 4326943 G C  0.5908 1471921 GGTCTC GGTCTC  0.271 2289194 ACC ACCC -2.965 4326980 T G -1.223 TTCGGA TTCGGA GATACT GATACT C (SEQ GTCTCT ID NO TCGGAG 008) ATACTC (SEQ ID NO 009) 1472069 G T -2.458 2289216 A G -0.1347 4326981 G A  2.192 1472155 C A -1.886 2289226 T G  0.2625 4326983 G A -2.551 1472705 G T  2.482 2289231 A G -0.6494 4327065 A G -0.7151 1472723 G A -0.720 2289252 T G  2.247 4327133 T G  0.7011 1472920 GTT GTTT -4.479 2289252 T C  0.2179 4327193 A C  1.22 1472970 C T -0.558 2411092 G T -4.486 4327323 G A -0.5768 1473246 A G -0.662 2504627 G A -0.2572 4327346 C A -0.2981 1473254 A C -1.558 2518809 A G -0.01745 4327448 A C -0.5885 1473835 G A  0.563 2518919 G A -0.2937 4328212 CGGGG CGGGG -1.818 GT T 1474200 ATT AT  0.428 2620945 G T -2.675 4399047 G C -0.1088 1475395 T C -3.499 2693848 G T -2.34 4399252 A G -0.2229 1475778 G A -2.152 2693851 G T -4.797 4399261 GCA GCC -1.756 1476105 G A -0.616 2693853 T G -2.529 4407794 G A -1.677 1476600 A T  1.003 2694792 G A  0.9544 4407866 C A  0.7704 1487556 C T  0.752 2694805 C A  1.707 4407927 T G -0.05012 1501971 C A  1.572 2726136 C T  0.2232 4407949 T G  0.357 157129 C T  0.290 2726338 T G  0.05506 4408124 C G  1.028 157214 G A -0.092 2726341 TGTTC GGGTT  1.021 4408138 T G -0.01963 157555 T G  0.490 2726341 TGTTC GGTTTG -3.828 4408150 A T -0.4527 GTTC (SEQ ID NO 010) 1674048 G A -0.319 273099 A G -0.1801 490696 T G  0.6564 1674248 T C -0.000 273508 T C -0.1608 495040 G A -4.984 1674356 A G -3.716 274030 C T -3.071 495757 T C -1.524 1674417 C T  1.584 274141 C T -3.411 496386 G A  0.643 1674709 T C -1.567 2751677 G A  0.4571 496666 C T -1.783 1674782 T C -0.637 2751953 C AG -0.05598 497389 CCAG CG -3.33 1674837 C T  0.005 2751960 A G  0.001925 512358 GCG GCCG -0.8782 1719904 C A  0.366 2751974 G A -0.1027 513468 T G  1.025 1719949 T C -1.879 2751974 GCCCG ACCCC  0.938 514344 G A -1.56 1758384 G A  1.314 2751984 T C  0.5663 514808 T G -0.5121 1758588 A G -0.250 2752122 G C -0.008562 515287 G A  1.199 1758596 T C -2.607 2876061 A C  0.1961 5311 G A -1.639 1759252 G T -0.538 2937360 T C  0.7362 538656 G T  1.057 1799759 T G -0.271 2939372 AG AC  6.916 538681 C A  0.9804 1816204 A G  1.611 2939373 G C  0.04322 540353 A C -0.0419 1833695 C G  2.051 2939609 C A -5.374 541439 G A -4.584 1833763 C T -3.473 2940725 G C  0.4757 5530 C G -2.373 1834177 A C -0.110 2940748 T C  0.5282 575503 G A -3.856 1834187 G C  1.934 2940758 A C  0.05618 575538 A G -0.06581 1849861 G A -0.149 2955203 C T -3.462 576016 A G -2.84 1850309 A C  0.659 2956336 T C  0.03141 576400 C T  3.759 1875457 T G  2.155 3020515 G T  0.3948 576660 T G -2.458 1875550 GA TT  0.757 3073685 C G  0.1367 576705 A G -1.258 1875550 GA TA  1.051 3272997 A G -0.5377 576710 C G -0.03793 1875576 G A -0.415 3273107 C A  0.4061 576718 CGA GGG  2.659 1875587 GGT CGG -0.074 3296271 T C -4.87 576742 GGT GGG -3.311 1875589 T G  0.016 3296300 C A  0.5481 5856 T G -2.881 1875618 TTTTG GTTTT  1.627 3296437 T G -0.2611 60373 T A  1.2 1875629 A G -0.956 3296639 ACC AC -0.05812 60551 A C  0.8874 1875670 C A  0.582 3296736 T G  0.1371 6144 A G -0.3711 1875902 T C -2.458 3296753 G C -3.645 615211 T G  0.02088 1875915 C G  0.975 3296792 G C -1.356 61543 A T -7.939 1876332 GGGC CGGG  0.663 3296843 A G  0.7089 616196 A C -2.472 1876420 T G  0.201 3296848 G A -0.3835 61898 C G -1.339 1876531 G A -1.361 3296962 G C -5.089 61924 C T  1.491 1877298 C G  0.092 3296999 T C  1.375 61988 C T -3.664 1877315 A G  0.057 3297010 G A -4.714 62801 C A  1.493 1877326 G C  0.297 3297018 C T  3.912 648774 C T -1.394 1877727 C T  1.119 3297704 G A  0.706 648992 C G -0.08657 1877831 A G -0.008 3326134 T C  0.2469 6576 G A -3.877 1877909 TGGGC GGGGG  0.132 345504 A C -4.584 6734 A G -0.2115 CGGT CGGG 1877947 G A -2.169 346563 C T -3.199 6794 A G -5.591 1877984 A G  0.916 3466562 G T -0.9245 6918 ATGTG TTGTT  0.969 1878570 T G -3.931 347221 G C -2.098 6973 G A -0.2529 1878619 GT GG  1.288 347256 C T -5.216 7268 C T  1.17 1878723 T G -0.005 347393 C T -5.038 7362 G C  2.115 1879531 GATG GG  3.735 347449 C G -2.458 7521 G T -0.5012 1879717 GGCTG GG -0.275 348381 C T -0.2188 7570 C T -0.3029 GTCGTT G (SEQ ID NO 011) 1879849 GC GG  1.393 349071 A G -2.285 7582 ACAG CCAC -0.4839 1879858 T G  1.752 349205 A C -4.584 7584 AG GC -2.188 1879864 GC GG  0.896 349520 A G -0.6133 760209 A G  1.788 1879870 TATTGG GATTTG  2.520 354606 C T -2.369 760308 G A -0.7744 GGT GGG 1880234 CGG CG -3.118 355004 C A -2.11 760480 G C  0.9946 1880402 G T -1.094 355082 C A -0.005737 760567 C T  0.7285 1881713 A C -0.252 355692 T G  1.374 761045 C T -0.05706 1882618 T G  1.855 355860 C G -2.955 761076 T G -0.08802 1882653 T G  0.100 3569344 G C  5.503 761093 G T -0.4355 1882958 T G  0.785 3569759 C A -0.3351 761100 C A  1.266 1883377 G C  3.029 3570229 C G -1.765 761101 A T -0.1552 1883716 T G  0.158 3570265 C G  1.228 761108 GG CT  1.085 1883784 C G -1.139 3570291 C A  1.073 761109 G T -0.9329 1883794 A C  1.029 3570298 A C  0.1995 761109 GA TT -0.6942 1884260 G A  1.045 3835223 C T -2.399 761110 A T -0.488 1917851 C A -5.003 3836116 G A -0.0129 761127 TC AT  6.353 1917998 G T -3.021 3986902 G A -0.3509 761128 C G -0.2549 1918010 C G  0.736 3986931 C A -0.4018 761131 G A -1.003 1918019 T C -1.416 403920 C T -0.2228 761135 GACCCA TACCTG -1.153 1918164 GGCGTT GGCGTT  0.864 404132 C T -0.3694 761139 C T -0.3809 CG CGCGTT CG (SEQ ID NO 012) 1918169 T G -5.282 404356 T G  0.4043 761139 C G -0.6814 1918336 CGG CG -1.298 405404 C T -1.914 761139 CA GG -1.266 1918340 C T -2.252 405479 G A -5.093 761140 A T -1.023 2053562 T C  2.979 4124351 C G -4.584 761154 TCGGC CAGGG -0.2556 2053589 C T -0.081 4125386 C G -0.774 761155 C G -0.9029 2101853 A G -3.826 4125415 A G -0.5558 761155 C T -0.8579 2101965 C T  1.080 4238963 C T -0.2097 761161 T C -0.9807 2102120 T C -0.298 4239274 C G -0.5186 761244 A G  1.143 2102289 C T -2.320 4239476 G T  0.6963 761268 A G -2.496 2102696 A G -1.348 4240661 T C  0.9266 761292 G A -0.1669 2102849 T C -0.694 4240678 T G -0.02568 761419 C T  0.8166 2102912 G C -2.505 4242075 G A  0.008024 761461 G A  3.177 2102949 T C -0.975 4242435 T G  0.7909 761528 C A  0.6516 2133859 C T -3.169 4243217 C G  0.822 761583 C T -0.1214 2133987 C T -0.393 4243221 C T  2.582 761973 C G  0.1424 2153742 A G  0.547 4243346 A G -0.1444 762399 G T -0.3968 2153819 C G -2.132 4243667 C G  1.301 762434 T G  0.005517 2154108 C T -1.962 4244631 A C  0.4376 762967 A G -1.443 2154232 A G  0.100 4245009 G A  1.117 7632 G A  1.974 2154329 G A -4.417 4246662 T C -1.364 764181 A G -2.492 2154695 C A -0.306 4247399 A C  0.7902 764673 A C  2.934 2154857 C G -0.039 4247402 T G  0.5033 764744 C T -0.02669 2154977 C T -0.000 4247429 A G -4.691 764924 G A -2.407 2155163 T C -0.347 4247429 A C -2.975 764948 T G -0.6006 2155167 GC CG -0.323 4247431 G C -3.305 765842 A G -2.063 2155168 C G -0.893 4247431 G A -4.054 766198 C A  2.744 2155217 C T  0.629 4247431 G T -3.479 766466 G C -0.1748 2155301 T G -0.596 4247469 A C -4.072 766485 T C -0.7597 2155430 T G -2.185 4247469 A G -3.855 7776 C G -1.169 2155648 T G  0.400 4247553 G C -3.215 779316 G T -2.458 2155741 C G -0.662 4247574 A C 0.4781 781687 A G -0.5226 2155801 C T -0.631 4247728 G C -0.93 781880 C T -0.6199 2288718 ATCTCC ATCTCC -1.376 4247729 G A -3.111 784696 C T  4.911 T TCTCCT (SEQ ID NO 013) 2288730 G T  2.555 4247729 G T -0.1692 7862 C T -0.5825 2288739 G C  0.943 4247730 G C -3.307 7892 GGCC AGCT -0.3082 2288771 CA CTA  0.479 4247730 G A -3.51 7914 C A -0.4223 2288779 C T -0.570 4247738 G C -0.7601 7965 C T -0.003783 2288782 T C -0.155 4247999 G A  0.2457 796747 T G -0.07686 2288805 G A -0.503 4248002 C A -3.278 797074 T G -0.3442 2288813 GGCCG GGCCG -0.633 4248003 A G -4.157 8075 G T -3.391 TCTGGC TCTGGC G (SEQ GCCGTC ID NO TGGCG 005) (SEQ ID NO 006) 2288827 C G  1.977 4248003 A C -0.7207 8164 C A  1.334 2288830 A G -0.309 4248024 A C -0.6607 8364 A G  2.04 2288844 A G -0.085 4249246 A C -0.5118 8435 C G -2.805 2288852 CACATC CC  0.207 4249518 A G -4.393 8486 T C  1.474 2288895 AGT AGGT  0.084 4257766 C T  0.1822 875005 T G  0.03749 2288926 A G -0.668 4259573 A C  0.05949 875532 C G -1.928 2288932 TGTACG TG -0.258 4260099 T G -0.2167 9162 C A -0.077 2288938 C G  0.547 4260769 G A -0.3879 9224 C G  1.146 2288942 GGTG GG  8.470 4260790 G A -0.5758 9289 T C  1.116 2289029 A T -1.555 4261150 T G -0.3523 931017 C T  1.532 2289030 T C -0.009 4269722 C A -0.7167 931443 C T -4.892 2289031 G A -3.441 4269731 C A -0.01996 9395 G A  0.6246 9591 G A -0.260 9846 C G -1.019

TABLE D Pyrazinamide weighted positions; threshold value: -3.426 POS RN SN W POS RN SN W 1128783 G A  0.602 2288892 AGC AGGC -0.471 1132004 A C -4.250 2288900 CGT CT -2.601 1136668 G T -0.484 2288902 T G -1.021 1136765 G A -0.442 2288920 C A -3.310 1237438 T G -0.324 2288926 A G -2.919 1237557 A C -3.728 2288927 GCC GCCC -3.542 1237627 C G  0.051 2288930 G C -5.261 1238171 A C -0.126 2288932 TGTACG TG -4.617 1416222 A G -0.245 2288933 G C -0.756 1416232 ACA GCC -0.020 2288942 GGTG GG -1.875 1471861 T A -2.499 2288945 G T -0.340 1471862 T G  0.487 2288952 C T  0.703 1471921 GGTCTC GGTCTC -1.956 2288953 C G -2.792 TTCGGA TTCGGA GATACT GATACT C (SEQ GTCTCT ID NO TCGGAG 008) ATACTC (SEQ ID NO 009) 1472359 A C -0.190 2288955 TT TAT -2.250 1472633 C T -0.908 2288956 T G -1.013 1472723 G A -0.315 2288971 C A -3.768 1472970 C T -4.142 2288985 TCCA TCCCCA -1.879 1473246 A G -0.570 2288992 TGG TGGG -4.745 1473912 C G -0.990 2289008 GCC GCCC -1.606 1474261 C T -2.342 2289029 A T -4.454 1474317 G T -1.874 2289030 T C -4.156 1474900 G T -5.093 2289031 G A -4.341 1475395 T C -2.860 2289031 G T -3.591 1475762 G A -0.395 2289039 C T -3.710 1476105 G A -3.552 2289049 AA ATA -3.163 1501986 T G -1.795 2289049 A G  0.071 157174 T C -0.229 2289056 CG CTG -1.091 1674248 T C -4.141 2289056 CGG CG -1.672 1674356 A G -2.694 2289090 T C -0.032 1674448 G A -3.253 2289090 T G -1.036 1674709 T C -3.944 2289091 G A -4.137 1719904 CAAA AAAC -0.335 2289091 G C -3.877 1758278 C T -0.565 2289092 GAA GA -2.879 1758596 T C -0.144 2289097 C T -3.556 1759252 G T  0.220 2289119 G C -1.008 1799599 A G  0.700 2289120 TAG TAAG -3.826 1800040 T G -2.718 2289137 CAG CG -2.174 1816204 A G  0.119 2289140 G C -3.698 1833594 C A -4.141 2289144 T A -2.018 1833626 A G -3.768 2289147 C A -1.589 1834859 G A -2.829 2289156 CGG CGGG -3.535 1875457 T G -0.152 2289162 A G -2.038 1875499 G T -0.185 2289163 GCGCG GC -3.922 GCGCC ACC (SEQ ID NO 14) 1875556 G C -0.195 2289164 CGC CC -1.396 1875562 G C -0.020 2289167 GGCGC GC -4.579 CACCG GTTACC GCCAG CGAGC CAC (SEQ ID NO 15) 1875573 C G -0.507 2289183 GCCAG GC -1.072 CGAGC CAC (SEQ ID NO 16) 1875576 G A -0.096 2289213 T G -0.937 1875587 GGT CGG -1.771 2289214 G A -3.974 1875670 C A  0.232 2289219 T C -0.245 1876531 G A -0.110 2289223 C G -0.355 1877831 A G -0.474 2289226 T G  0.061 1877909 T G  0.230 2289231 A G -0.681 1877913 CCGGT GCGGG -3.149 2289239 C T  0.672 1878542 A C  0.430 2505553 A G  0.428 1878586 G A -2.746 2518151 A C -0.680 1878829 T C -0.342 2621145 A C -3.889 1878834 G A -4.075 2622182 C A -0.674 1879399 G A -0.081 2693848 G T -2.146 1879517 G T -4.576 2693851 G T -4.381 1879531 GATG GG  0.385 2693853 T G -2.383 1879660 G A  0.645 2693890 G C -2.160 1879680 G T -0.054 2694942 G A  0.814 1879685 T G -0.057 2714566 A G -0.076 1879745 T G -2.077 2714977 T G -0.942 1879842 TGGT TGGG -0.322 2715330 C T -2.699 1879863 G T  0.473 2726338 TGGTGT GGGGG -0.663 TC TTT 1879870 TATTGG GATTTG  0.677 2726341 T G  0.003 GGT GGG 1879878 TGC GGG -2.438 2726537 G A -3.133 1880351 A C -3.842 2751677 G A -0.030 1882854 C G -3.755 2751953 C AG -1.092 1884305 T G  0.244 2751987 G C -0.079 1885336 A C -0.792 2752005 A G  0.908 1886027 G A  0.888 2752046 G A -1.246 1886509 T G -3.147 2752059 G C  0.805 2053562 T C -0.025 2874086 G A -4.576 2053589 C T -0.456 2939372 AG GC -0.939 2101915 A G -2.476 2939373 G C  0.796 2102188 C A -0.724 2939609 C A -4.682 2102417 G A -0.695 2940725 G C -2.193 2102466 C T -1.330 2956336 T C  0.282 2102486 G C  0.931 3073685 C G -3.552 2102536 C T -0.978 3074073 C T -3.754 2102912 G C -1.983 3272251 T G -0.023 2133987 C T -4.614 3272659 T A -0.203 2153899 T G -0.935 3272997 A G -0.302 2153906 T C -0.608 3273164 T G -0.547 2154332 A T -1.945 3296639 ACC AC -0.079 2154354 CAC CC -4.377 3296753 G C -2.859 2154695 C G -3.217 3296843 A G  0.067 2155168 C G -0.619 3296848 G A -0.559 2155168 CTGGT GTGGC -4.792 3296925 GCA CCCGC 0.345 C 2155169 T C -0.898 3296927 A C -0.271 2155296 G A -0.548 3296962 G C -4.518 2155563 G T -2.702 3297111 T G -0.900 2155687 T C -2.823 3326338 A C  0.452 2288704 C A -1.757 346205 C T  0.576 2288714 GCG GCCG -0.923 3466622 G T -2.338 2288718 ATCTCC ATCTCC -2.879 3470150 G A -0.288 T TCTCCT (SEQ ID NO 013) 2288724 TCC TCCC -2.571 347221 G C -0.478 2288727 AGCG AG -3.784 347393 C T -4.511 2288737 CGGT CGGGG -2.763 3479470 G A -4.576 T 2288742 G A -2.119 349071 A G -2.248 2288746 CGG CG -0.996 349151 A G -1.023 2288757 C T -3.637 349520 A G -0.372 2288761 CT CGT -1.481 3513724 C T -2.950 2288771 CA CTA -3.393 354606 C T -1.962 2288778 ACC ACCC -4.562 355860 C G -2.409 2288780 C A -3.380 3569344 G C  0.132 2288782 T C -4.109 3569447 C T -0.848 2288785 TGG TGGG -3.030 3570220 T C  0.263 2288789 CAA CAAA -2.181 3570258 A C  0.253 2288791 AGC AGGC -3.504 3570322 T C -3.219 2288792 GCC GCCC -4.518 3570337 A C -0.057 2288797 TGCGTA TGCGTA -1.880 3835223 C T -0.491 CCGCG CCGCG (SEQ ID CGTACC NO 017) GCG (SEQ ID NO 018) 2288813 GGCCG GGCCG -2.171 3836116 G A -1.477 TCTGGC TCTGGC G (SEQ GCCGTC ID NO TGGCG 005) (SEQ ID NO 006) 2288820 T G -0.520 403417 C A -2.146 2288821 G A -2.148 405479 G A -4.688 2288823 C G -1.872 4124351 C G -4.511 2288827 C G -3.564 4124906 A C  0.072 2288834 ATC ATTC -4.256 4238456 G A -0.498 2288836 C T -1.949 4239863 A G -2.609 2288847 CCGACC CC -4.499 4242369 G A -0.802 ACATC (SEQ ID NO 19) 2288850 ACCA ACCCCA -2.814 4243325 T C -0.030 2288850 ACC ACCC -3.560 4243692 G A -0.766 2288851 CCAC CCACAC -3.736 4245311 C G -2.320 2288852 CACATC CC -4.433 4245850 C T -0.411 2288852 CACATC CA -4.176 4246833 A G -4.315 GACCTC ATCGA (SEQ ID NO 20) 2288859 ACC AA -2.621 4247429 A G -0.846 2288860 C A -0.220 4247431 G A -0.343 2288864 A T  0.059 4247469 A C -0.800 2288868 A C -0.543 4247763 T C -3.532 2288885 C T -0.487 4247862 T G -0.138 2288886 C T -1.533 4248003 A G -0.489

TABLE E Streptomycin weighted positions; threshold value: −2.501 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC −3.307 2412085 A C 0.03125 4407931 A G −2.556 1084899 C T −1.268 2621640 G A −0.3229 4407940 A G −4.711 1131738 T C −3.258 2714460 C T −3.597 4407949 T G −2.784 1132890 C T −0.333 2715016 C T 0.5003 4407955 C G −1.882 1237557 A C −3.307 2752168 G T −2.701 4407979 G C −4.377 1238164 A C −0.222 2876174 G A −0.2572 4407982 A T −1.934 1471861 T A −1.934 2937665 C A 2.861 4407994 C T −4.925 1472015 A G −1.400 2939373 G C 0.1764 4407997 C T −3.444 1472069 G T −3.307 2939609 C A −4.335 4408009 ACC ACCC −2.98 1472102 G A −0.465 2939891 G A −0.8905 4408048 C A −1.669 1472127 CGG TAC 4.475 2955145 G A −0.6694 4408059 A T −4.94 1472143 GA GTA −3.112 2955957 A C −0.1259 4408061 GCC GC −4.197 1472359 A C −5.201 2956571 G C −3.307 4408064 G A −2.236 1472359 A T −5.186 3074103 G A −5.016 4408069 C T −4.536 1472362 C T −4.232 3074246 CGTGCT CGTGCT −0.6583 4408087 CGG CG −4.297 CGTGC CGTGGT (SEQ ID GCTCGT NO 021) GC (SEQ ID NO 022) 1472418 T C 0.688 3272997 A G −2.493 4408100 GCCCC GCCCC −4.933 CG G 1472548 A G −4.951 3296639 ACC AC −1.609 4408102 C A −3.7 1472723 G A 0.607 3296792 G C −1.488 4408115 CGG CG −5.634 1472750 C A −0.979 3296843 A G 1.422 4408161 CGG CG −3.621 1472751 A G −4.137 3296962 G C −4.921 491028 C T 2.099 1472753 A C −0.462 3297704 G A −0.1068 511170 C G −0.7074 1473170 A C −1.642 3326811 C G −0.06629 513282 G A −3.307 1473246 A G −0.182 3388838 G A 2.67 513687 C T −1.763 1473254 A C −3.128 346309 C G −2.229 514306 C A −0.3984 1473870 G A −0.068 346399 T C −2.632 514357 T A 4.212 1474007 A C −0.652 3470150 G A 0.4771 514657 T G 0.00495 1474277 C A −0.642 347449 C G −3.307 514684 C T 1.008 1474298 T G 0.975 347650 C T −0.08985 514911 T G −1.425 1474527 T G −4.921 3514512 G C 0.1345 515190 G A 0.5394 1474740 G T −0.801 355677 G T −0.9013 5548 A G −3.464 1474852 T C −1.227 355745 C T −0.6918 5722 G T −4.92 1475343 A G −4.800 3570207 G A 0.5976 575503 G A −3.656 1475479 C G 0.671 3723383 G T −5.091 575562 T C −2.541 1475510 A G −4.920 3836358 G C 6.269 576057 TGGT TGGGGT −1.426 1475778 G A −5.092 403565 T G 0.1425 576372 C G −1.435 1476016 T C −4.920 404132 C T −0.1892 576526 C T −1.416 1476056 G A −0.066 404356 T G 9.469 576564 T G 3.904 1476105 G A 3.738 4238675 C T −0.1677 576660 T G −3.307 1476704 GCCCC GCCCC −0.041 4239965 G A −4.92 576710 C G −0.1274 CCG CG 1502120 C A 0.133 4239976 G A −0.06628 576766 G A −0.5185 1673604 G A −0.692 4240562 A C −0.2974 6016 C G −2.956 1673949 G A 1.503 4241281 G A −2.686 60875 G A −2.044 1674263 T C −0.545 4241292 T G 8.077 6122 G A −5.066 1674481 T G −1.032 4242312 G A 0.6754 614975 G C −0.1796 1674782 T C −0.141 4242595 C A −4.951 615752 C G 0.1415 1674981 C T 0.806 4243667 C G −0.7131 615791 G C 4.246 1719877 A G −2.059 4243969 T C −1.474 616092 G T −0.01828 1759422 A G 1.151 4244069 C T 2.897 6302 G T −4.017 1799713 A C 0.299 4244832 G A −0.3032 648774 C T −1.578 1800177 G A −2.087 4245075 G C −2.681 649235 C G −1.066 1817289 C T 0.359 4246869 G A 1.008 6794 A G −4.769 1833594 C A 3.001 4246941 C T −1.486 6878 T C −0.2723 1834953 C G 1.000 4247070 T C −3.258 6937 G T −4 1849051 C T −0.067 4247429 A G −0.6171 6989 G C 1.774 1875556 G C −0.154 4247431 G C −0.07703 7219 C T −0.06628 1875562 G C −0.172 4247513 T C −0.6503 7362 G C 0.041 1875587 GGT CGG −1.780 4247574 A C −0.05156 7510 A G −2.287 1875754 A C −1.859 4247999 G A 2.769 7570 C T −0.3531 1877231 TGGGT GGGGG −1.354 4248003 A G −0.03969 7570 C G −0.3752 1877744 A C −0.056 4248758 C T −0.8352 7581 GACAG TGCAC −1.934 1877918 T G −1.669 4249007 C T −4.2 7583 CAG CAC 4.559 1879244 T C −0.666 4249327 G A −4.343 760404 C T 8.16 1879316 C T −5.066 4257095 A C −1.978 760480 G C −0.08093 1879742 C G −2.340 4258223 T G −1.033 760640 C T −2.574 1881059 C T −4.503 4258955 T G 0.02962 761110 A T −0.09844 1881536 A C −0.643 4259418 A G −0.06712 761114 GAACAA GAACC −0.1462 CC 1881540 A C −0.011 4259507 A C −0.3503 761127 TC CA 3.026 1882475 G A −2.112 4269606 A G 0.09195 761139 C T −0.1047 1882831 T C 0.314 4308852 G T −3.22 761139 C G −0.4019 1883039 A C 0.108 4326135 G T 4.777 761155 C G −0.6907 1883378 A G −0.415 4326279 ACACC ACACCA 0.4032 761155 C T −0.7283 CC 1883766 T G −0.188 4326391 C T −5.073 761161 T C −0.01422 1883768 A G −0.253 4326620 T G 3.444 761277 A T −1.57 1884469 T G −0.338 4326695 A T −3.573 761382 A T −1.814 1885385 T G −0.074 4326842 T G −0.009964 7615 T G −3.307 1885562 T C −1.374 4326864 T C −3.778 761889 G C −2.882 1885835 A T 0.829 4326917 G A −2.418 762089 G C −0.1007 2054069 G T −4.701 4327067 A C −2.745 762179 C T −0.5709 2101769 C A −2.318 4327229 A G 0.07244 763155 G C 1.869 2102207 C T −0.652 4327301 T G −0.7666 763277 A T −2.637 2134064 G A −1.424 4327333 CAA CA −2.986 764617 C T 1.189 2154461 CG CTG −0.830 4399385 C T −0.0238 766645 A C −0.1773 2154486 G T 3.833 4399794 G A −0.6918 766978 C T 1.454 2154695 C G 1.362 4403351 G A 0.001327 7705 C G −0.03499 2154739 A T −4.387 4403900 A G 0.1405 7776 C G −3.004 2154746 CAA CA −1.883 4407596 C G −4.769 779279 C T −0.8469 2154834 G C −0.237 4407686 C A −4.8 781687 A G −5.212 2155163 T C −2.707 4407713 CTT CT −5.356 781768 A C −3.258 2155167 GC TG −0.547 4407732 C T 0.9338 781822 A G −5.343 2155168 C G −1.689 4407748 A G 0.1723 781822 A T −3.838 2155168 C T −0.557 4407790 G A −4.6 781822 A C −2.717 2155648 T C −0.031 4407790 G T −4.221 7879 A G −0.6029 2155746 G A 2.732 4407796 G T −1.879 7914 C A −0.07119 2155801 C T −0.023 4407796 G C −3.177 796747 T G −1.174 2155968 C T −2.366 4407802 G A −4.951 798355 G C −0.06799 2223293 T C −1.426 4407807 G A −3.712 8056 G T −0.9141 2288730 G T 5.051 4407816 GCC GC −5.878 8554 G A 0.2409 2288785 TGG TGGG −0.548 4407830 G A −4.672 8646 C G −4.751 2288953 C G 2.937 4407846 GGCGC GGCGC −4.956 875532 C G −3.307 GCC C 2289031 G A −3.904 4407850 C A −4.885 875772 G A −0.2079 2289038 C A −3.956 4407851 GCCCC GCCCC −4.1 8806 A G 0.2318 CG G 2289068 G C 0.272 4407851 G T −2.117 891788 C G −2.299 2289140 G C 0.009 4407851 GCCCC GCCCC −2.275 9276 C T −0.5072 CG CCG 2289144 T A −2.713 4407876 GCC GC −5.199 9437 G A −0.5645 2410821 C T −0.097 4407925 G A −3.32 9724 A T −2.681 9803 C T −0.032

TABLE F Ciprofloxacin weighted positions; threshold value: −4.815 POS RN SN W POS RN SN W POS RN SN W 1472621 G A −0.416 3326232 G C −0.7143 7582 ACAG GCAC −3.27 1476442 T C −0.611 347221 G C −1.797 7585 G C 0.1673 1879388 C T −0.523 4247431 G C −0.4812 760493 C A −0.6532 2154695 C G −0.017 4247431 G A −0.318 761277 A T −1.293 2288771 CA CTA −5.862 4249403 A C −0.2356 761293 T C −0.4454 2289052 A C −0.476 4326231 CAA CA −0.7394 766070 C T −0.6943 2620781 T C −0.506 4408100 GCCCC GCCCC −0.3498 7960 T G −5.49 CG G 2937779 C T −0.267 7521 G T −5.199 875309 T G −5.599 9224 C G −2.581

TABLE G Moxifloxacin weighted positions; threshold value: −2.547 POS RN SN W POS RN SN W POS RN SN W 1084993 G C −0.011 2288771 CA CTA −1.488 4261145 A C −0.3533 1473835 G A −0.399 2726339 GGT GGG −0.1374 4308881 C T −0.1004 1759252 G T −1.000 3569508 G A −0.3697 4326045 CCTC CCTCTC −0.5565 1834836 T C −0.248 403406 A C −0.4319 4326333 C G −0.3491 1875869 T G −0.129 4241022 C T −1.488 4399185 C T −0.3303 1877968 C G −0.148 4242369 G C −0.3386 4399629 C G  −0.2734 1884026 C T −0.224 4247249 G C −0.288 497254 T C −0.7099 2053682 C T −0.002 4247730 G A −0.3273 538621 C G −0.3397 2053759 C T −0.271 4249401 T G −0.4664 541262 A G  −0.1039 2154695 C G −0.506 4249664 A C −0.2223 7582 ACAG GCAC −0.09353 2155168 C G −0.165 4259744 G C −0.2165 761100 C A −0.527 779369 A C −0.984 801174 T C −0.397

TABLE H Ofloxacin weighted positions; threshold value: −1.774 POS RN SN W POS RN SN W POS RN SN W 1085605 C T  −2.724 2289156 CGG CGGG −0.001581 538656 G T −0.5569 1472058 T G −0.406 2289163 GCGCG GC −0.4793 538681 C A −1.203 GCGCC ACC (SEQ ID NO 014) 1472069 G T −2.724 2289223 C G 2.927 5555 G A −4.358 1472155 C A −2.707 2289226 T G 0.1411 615211 T G 0.02529 1472723 G A −0.221 2519280 C T 1.793 62904 G A −0.02509 1472920 GTT GTTT −0.553 2714885 GAA GA 4.618 648774 C T −2.261 1473012 G A −5.674 2726636 G A −0.1754 6620 G A −5.415 1473246 A G −0.656 2751804 C T 1.26 6620 G C −4.534 1473254 A C −2.080 2751978 G C −0.4759 6734 A T −5.343 1473344 T C 9.306 2939657 T C 0.1112 6734 A G −0.05677 1475570 AATGCC TTTACC −0.124 2956571 G C −2.724 6735 A C −0.05309 C T 1487974 ACCC CCCG −0.654 3074230 T C −2.567 6735 A G −5.747 1488006 C G −1.610 3272997 A G −0.3665 6736 C A −4.197 1674709 T C −2.677 3296639 ACC AC −0.05368 6736 C G −4.951 1674782 T C −0.226 3296928 CCA CCC −1.336 7457 T A 1.966 1758588 A G −0.218 3296956 C T −6.045 7495 GCC GCCC −2.724 1816017 T G −0.620 3297018 C T −1.367 7563 G T −5.518 1833909 A C −0.145 346275 C G 0.6163 7564 G C −6.123 1834177 A C −0.014 3514392 T G 7.944 7570 C T −5.775 1875902 T C −1.975 354822 G A −0.6586 7570 C G −3.652 1876603 C G −2.953 355677 G T −0.2409 7570 CGT TGC −5.177 1879890 C T −2.641 355709 ACC ACCC 1.296 7572 T C −6.169 1883716 T G 0.018 3569277 CTTG CTTT −0.5705 7581 GACAG AACAC −5.086 1884817 A G 2.649 3569325 G C −1.213 7581 GACAG CACAC −1.591 1886509 T G −2.507 3569731 T G −0.5217 7581 GACAG TACAC −5.372 1917972 A G 0.529 403358 A G 1.702 7581 GACAG GACAC 2.838 1918137 AGCG AGCGC −0.318 404356 T G 2.843 7581 GACAG TGCAC −4.509 G 2101853 A G −1.533 4125409 T C −0.5124 7581 G C −3.872 2102492 T C 2.261 4238092 A G −1.487 7582 ACAG GCAC −5.612 2133987 C T −3.043 4247429 A G −0.03336 7582 ACAG CCAC −6.135 2153852 T G −0.406 4248003 A G −0.2313 7582 ACAG ACAC 4.483 2154695 C A −0.165 4257750 CGG CG 3.084 7582 ACAG TCAC −4.328 2154695 C G 0.086 4269271 A G −0.03665 7582 A C −5.026 2155168 C G −0.406 4307609 T G −0.3574 7582 A G 2.073 2155430 T G −2.510 4307617 A C −0.568 7583 CAG CAC 3.761 2155563 G T −0.516 4326083 T C −0.01748 7585 G C 0.8611 2155648 T C −0.428 4326087 GTA GA −0.4221 760978 A G −0.322 2155687 T C −5.483 4326251 TAATTC TAATTC −6.805 761110 A G −0.5045 A AATTCA (SEQ ID NO 023) 2223293 T C −0.314 4326282 C A −2.724 761131 G A −1.16 2223448 G A 3.028 4326625 GCC GC 8.419 761155 C T −0.287 2288805 G T −0.476 4326801 GCT GCCT −0.8729 761292 G T 5.647 2288835 T C 8.082 4326879 C T 8.546 7615 T G −4.844 2288852 CACATC CC −1.144 4327333 CAA CA 2.408 762399 G T −3.589 2288852 CACATC CA −0.445 4399261 GCA GCC −4.209 763123 T C −0.6369 GACCTC ATCGA (SEQ ID NO 020) 2288919 C T −4.002 4407781 G T −0.2273 763320 G C −5.301 2288942 GGTG GG 9.363 4407927 T G −0.01711 764617 C T 1.998 2288988 A C 2.125 4408100 GCCCC GCCCC −0.7626 7776 C G −2.77 CG G 2289039 C A −0.040 490751 T G −0.4575 779350 G A 0.795 2289049 AA ACA 1.874 514357 T A −2.312 784125 G C −1.664 2289096 T C −0.242 514390 A C 9.738 796747 T G −0.2752 798355 G C −0.034 875532 C G −2.724

TABLE I Amikacin weighted positions; threshold value: −4.729 POS RN SN W POS RN SN W POS RN SN W 1136668 G T −1.482 1879849 GC GG −2.401 3296925 GCACCA CCCCCC −4.413 GCCCCA (SEQ ID NO 030) 1473246 A G −6.101 1880429 T G −0.2512 3296932 C A −2.458 1473247 C T −3.235 1881922 C G −0.3283 3570220 T C −0.1187 1475703 ACGAT GCGAA −0.824 1884305 T G −0.1133 3723401 G A −0.1123 1476212 T G −0.638 2155168 C G −0.1161 4237971 A T −0.5922 1719692 A C −0.529 2155687 T C −5.581 4238675 C T −0.2387 1850310 G C −0.104 2289111 A C −4.197 4399236 GGAGG GGGGG 1.623 CC CGGGA GGCG (SEQ ID NO 024) 1875556 G C −0.167 2726338 T G −0.1279 4399253 GC GG −4.429 1875562 G C −0.088 2726339 GGT GGG −2.483 614975 G C −0.1446 1875577 T G −0.982 2939372 AG GC −0.02616 6232 C A −0.6646 1877866 G C 1.707 2940714 A C −0.2417 761135 GACCCA TACCTG −2.419 1879685 T G −1.360 3272659 T A −1.407 761535 C G −1.545 766645 A C −0.180 781687 A G −0.113

TABLE J Capreomycin weighted positions; threshold value: −1.531 POS RN SN W POS RN SN W 1472172 T C 0.118 2155648 T C −0.223 1472337 C T 0.288 2155687 T C −1.184 1472362 C T −0.106 2288850 ACCA ACCCCA 0.456 1472753 A C 0.057 2288953 C T −0.061 1472793 A T 0.132 2289228 A G −0.442 1473246 A G −0.887 2519176 G A 0.102 1474324 C T −0.900 2621058 G A 0.012 1476481 T C 0.032 2714109 G A −0.033 156736 C T −1.264 2714846 C T 0.014 1674162 C T 0.187 2726338 T G −0.079 1674481 T G 0.135 2726339 GGT GGG −0.073 1757844 T G 0.006 2874707 C G −0.341 1758180 T G −0.263 2876062 CCT CCC −0.068 1759252 G T −1.302 2939017 T G −0.204 1816011 T G −0.065 2956497 A C −1.092 1816983 C T −0.128 3073868 T C 0.007 1848682 G T −0.108 3273102 C T −0.160 1851759 T G −0.297 3296843 A G 0.030 1875423 GGGG CGGA −0.793 3465987 G A −0.859 1875528 C G −0.320 3466525 T G 0.102 1876202 T G 0.064 347007 C G 0.019 1876332 GGGC CGGG −0.187 354606 C T −0.909 1877652 G A −0.329 3835465 T A −1.300 1878562 T G −0.378 3977610 C G 0.052 1879841 T G −0.060 4125398 T G −0.102 1880574 T C −0.167 4229168 GA GC −0.207 1883750 T G −0.206 4238632 T G −0.957 1885872 T C 0.041 4238972 C G 0.027 1885888 AATA GATG −0.096 4239476 G T −0.290 1917851 C A −0.037 4240153 G A −0.827 1918230 C A −0.772 4243963 T G −0.110 2101850 A C −1.424 4249408 G A 0.066 2153807 A C −0.004 4249583 G A 0.011 2155168 C G −0.028 4256011 G A −0.243 2155541 A G −0.085 4257220 A G 0.120

TABLE K Kanamycin weighted positions; threshold value: −3.033 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC −3.632 2288805 G T −5.032 4326855 G C −0.04238 108113 T G 1.700 2288824 GCACAC GC −0.7879 4326943 G C 0.03236 AATGAT C (SEQ ID NO 025) 1084174 C T −1.002 2288835 T C −1.406 4327132 GTT GT −1.07 1084280 A G 0.627 2288839 T G −0.2695 4327323 G A −0.09909 1084814 A C −0.835 2288883 A G −4.01 4328212 CGGGG CGGGG −0.8349 GT T 1084836 T G −0.785 2288938 C T −3.261 4398852 C T −2.862 1472069 G T −3.632 2288942 GGTG GG 3.59 4399683 C G −0.3013 1472621 G A −1.451 2288956 T C −0.4191 4403597 G A −3.134 1472920 GTT GTTT −4.694 2289040 A C 0.8196 4407927 T G −0.05477 1473131 G A 2.843 2289052 A C −1.59 495040 G A −2.853 1473246 A G −5.884 2289058 G A −0.6329 497491 G A −0.1604 1473247 C T −5.236 2289081 G T −0.8971 514357 T A 3.147 1473329 G T −2.156 2289090 T C −4.77 540097 T A −0.9936 1474234 G A −0.920 2289092 GAA GA −3.982 540587 G A −3.982 1474584 C G 2.733 2289100 T C −3.779 541262 A G −3.39 1474833 G T −2.644 2289103 T C −0.5849 575688 CGG CG −4.189 1475816 CA GG 0.079 2289119 G C 4.153 575834 T C −0.6272 1491272 G A 0.069 2289218 G T 1.856 576031 TGG TG −4.045 1501301 C T −8.326 2289254 C A 1.014 576273 CGG CGACG −3.978 GACTGG TCTGGC TTCACC G (SEQ ID NO 026) 1502561 C A −2.865 2505553 A G −4.87 5849 C A 1.82 1502745 A G −2.641 2620781 T C −0.7788 60373 T A 0.5306 1674417 C T 0.560 2693846 T G 0.3064 61178 C T −5.453 1674837 C T −5.246 2694792 G A 0.3661 648774 C T −3.265 1758588 A G −0.426 2694909 G A −4.279 6579 C T −0.1187 1817357 T G −2.800 2714130 C G −1.068 6817 G A −0.1101 1850557 A G −0.414 2714610 GAG GAAG −4.01 7495 GCC GCCC −3.474 1875439 T G −1.992 2715319 AG ACG −2.783 7570 C T −0.5245 1875509 A C −2.645 2751804 C T 0.4874 7572 T C −0.4159 1875902 T C −3.628 2752085 GC AA −2.28 7581 GACAG GACAC −4.01 1876559 C T 1.482 2939816 T C 1.07 7582 ACAG CCAC −0.005512 1876886 T G −2.228 3296753 G C −5.453 7583 CAG CAC 0.9808 1877624 G C −3.531 3296848 G A −4.509 7584 AG GC −0.2459 1878416 A C −3.552 3388522 C T −2.956 760461 C T −3.324 1879682 T C −2.861 346275 C G 0.9186 761110 A G −0.3047 1879713 G T −5.136 349054 C T −2.553 761155 C T −0.2511 1879878 TGC GGG 0.777 349331 G A −4.415 761161 T C −0.1584 1882933 T A −3.552 354679 C T −0.3462 761225 C T 2.469 1883179 G A −3.758 355846 T C 3.557 761268 A G −0.5828 1884110 C G 1.839 3835223 C T −1.736 761314 T C −0.7695 1884260 G A 0.113 3986931 C A −1.854 762285 C T −0.6924 1885341 A G −3.776 403448 C T −2.38 763277 A T −4.307 1885385 T G −0.003 403565 T G 0.06394 763438 G T −2.228 1886275 T C −1.264 403980 G A 0.4496 763571 GTGCG ATGAAG 0.6689 CTT TA 1917991 CGA CGGA 2.091 404130 T C −0.2474 764674 G T 1.266 1918029 C A −1.109 405812 T C −0.8692 764703 A G −3.304 2101853 A G −3.226 4124906 A C 0.02798 764724 T C −3.802 2101965 C T 0.451 4125386 C G −3.082 764822 G T −0.2686 2102417 G A −4.203 4125421 A G −2.829 764841 T C −1.032 2102912 G C −3.457 4243346 A G −0.9241 764918 G T −0.1229 2153852 T G 2.929 4246734 T G −0.1134 764925 G A −1.744 2154239 T C −0.256 4246833 A G −5.453 764931 C T −3.261 2154461 CG CTG −5.135 4247429 A G −0.7102 764948 T G 0.5548 2155168 C G −0.211 4248254 A G −4.585 781709 G T 2.296 2155430 T G −3.550 4257673 G A 4.342 782750 T C −5.453 2155648 T G 0.505 4269298 A G −0.5288 783404 A C −3.532 2288703 A C −1.328 4308395 G A −0.1075 784557 GAA GAAA 2.354 2288704 C G −0.020 4326120 GCG GG −2.678 784696 C T 1.757 2288724 TCC TCCC −0.660 4326279 ACACC ACACCA −1.455 7930 C T −0.5771 CC 2288778 ACCC ACCCCC −4.319 4326282 C A −3.632 800940 C G −1.702 2288782 T C −0.152 4326705 GCC GC −5.636 801019 A G −4.512 2288785 TGG TGGG −0.131 4326718 GGCG GGCGC −0.4992 875532 C G −3.632 G 9065 C A −3.010 931306 G C −1.857

TABLE L Prothionamide weighted positions; threshold value: −0.551 POS RN SN W POS RN SN W POS RN SN W 3272251 T G 0.102 4258428 C G −0.1321 4307617 A C 0.02583 783585 G A −0.244

TABLE M Ethionamide weighted positions; threshold value: −2.589 POS RN SN W POS RN SN W POS RN SN W 107937 ACC ACCC −2.881 2693848 G T −0.7518 4326801 GCT GCCT −4.616 1084335 G C −0.710 2693851 G T −0.5122 4326833 GACA GA −4.65 1085028 C G −1.238 2693853 T G −0.9397 4326858 G A −4.718 1085705 G C −0.057 2693934 T C −0.02244 4326964 GTC GC −1.913 1128074 A G −0.514 2694909 G A −0.1503 4326994 CGG CG −3.73 1132004 A C −0.967 2714308 G A −4.551 4327027 C A −3.543 1133169 T G −0.470 2726287 G A −3.075 4327033 G C −3.237 1138013 G A −0.415 273099 A G −1.703 4327091 GCG GCCG −1.829 1237205 A C −0.047 273449 C A −1.049 4327132 GTT GT −2.711 1461309 C T −0.192 274030 C T −1.186 4327192 GATTCC GATTCC −3.934 A ATTCCA (SEQ ID NO 027) 1472069 G T −2.881 2832239 CGG CG −1.572 4327231 GA GTA −4.292 1472723 G A −1.511 2873971 A C −0.09585 4327267 C T −4.309 1472753 A C −2.195 2937134 G A −1.76 4327269 AGGG AGGGG −2.86 G 1473123 A G −1.550 2939020 A T −2.825 4327294 G T −3.525 1473246 A G −0.121 2940719 A C −0.009038 4327325 TAA TA −3.936 1473254 A C −2.184 2956379 C T −1.751 4327333 CAA CA −3.935 1473329 G T −0.200 3073979 G A −1.953 4327334 AAATCC AC −0.08139 1475395 T C −3.269 3074246 CGTGCT CGTGCT −4.03 4327340 C T −1.155 CGTGC CGTGGT (SEQ ID GCTCGT NO 021) GC (SEQ ID NO 022) 1475778 G A −1.561 3272273 C G −0.1343 4327363 CTT CT −3.845 1476114 T C −4.177 3272700 T G −0.06887 4327404 G A −4.291 1476382 A G −0.643 3296115 A C −0.5959 4327441 GCC GC −3.223 1500988 C T −0.554 3296271 T C −3.287 4328212 CGGGG CGGGG −2.268 GT T 1502561 C A −1.751 3296843 A G 0.5174 4399181 T C −0.1061 1502745 A G −1.559 3296874 T G −0.2851 4399683 C G −0.8073 1674356 A G −3.591 3296886 G C −0.08439 4407790 G T −1.061 1718779 A C −0.397 3296928 CCACCG CC −0.7024 4407794 G A −1.792 CCAGC (SEQ ID NO 003) 1758384 G A −1.091 3388522 C T −1.765 4407798 C A −0.2267 1758596 T C −0.601 345504 A C −1.399 4408061 G T −0.503 1816078 A G −0.038 346045 G C −0.9491 4408174 G A −1.273 1816098 T G −0.125 346205 C T −0.6064 495040 G A −1.57 1816122 T G −0.103 346563 C T −3.252 511087 A C −0.1636 1816983 C T −1.441 347256 C T −2.901 511546 G A −0.9667 1833594 C A −3.251 347393 C T −3.288 512294 T G −0.1516 1833626 A G −4.061 349071 A G −0.9593 512344 C G −0.8387 1833909 A C −1.504 349205 A C −1.548 512610 C T −0.5648 1833909 A G −3.473 354535 T C −0.2019 514344 G A −1.536 1875499 G T −3.269 354586 T C −4.74 514404 C T −0.4633 1875569 TAGGC GAGGG −0.357 354606 C T −0.8001 514808 T G −0.06641 1875589 T G −0.308 355004 C A −3.269 5311 G A −0.7291 1875629 A G −0.824 355860 C G −3.269 538648 T G −1.76 1875674 A C −0.678 3569694 T C −0.2811 540358 ACCCA CCCCC −0.04754 1875771 G A 1.711 3570229 C G −2.312 541201 A G 0.2103 1875902 T C −2.881 3835223 C T −0.8169 541439 G A −3.251 1876531 G A −0.482 3836358 G C 1.375 575538 A G −4.584 1876569 G T −1.245 3986902 G A −0.3308 575660 CCCG ACCC −4.177 1876603 C G −0.812 403565 T G 0.01708 575688 CGG CG −4.497 1877154 G A −2.055 404130 T C −0.8468 576439 G T −3.559 1877727 C T 0.078 405479 G A −3.251 576699 A G −0.4055 1877921 G T −0.651 405665 T G −0.7775 61543 A T −3.313 1877947 G A −0.459 4124351 C G −3.029 615830 T G −0.416 1878037 T G −0.759 4228612 T G −0.1715 616196 A C −1.126 1878101 A G −1.585 4238062 TGGT GGGG −3.288 61898 C G −1.338 1878272 T G −0.128 4241699 A G −3.667 61988 C T −1.591 1878395 A G −1.090 4243346 A G −0.6673 6358 C T −3.897 1878570 T G −2.876 4243709 C T −1.683 648774 C T −2.409 1878711 A G −0.372 4245825 G A −2.73 6529 G C −2.161 1878723 T G −0.299 4246569 C T −0.7243 6579 C T −0.2419 1879418 T G −0.353 4246662 T C −2.297 6579 C A −3.543 1879826 C G −0.391 4247431 G A −0.3973 6620 G A −0.3627 1880396 T C −1.741 4247597 T G −0.2415 6639 C T −3.925 1880402 G T −1.531 4248320 G A −4.104 6877 G T −0.06457 1880444 T G −0.854 4259573 A C 0.02039 7088 G T −3.135 1880629 A T −0.033 4260790 G A −0.09451 7151 C T −3.786 1881536 A C −0.987 4261145 A C −0.3147 7316 G T −3.462 1881713 A C −0.590 4261150 T G −0.03143 7495 GCC GCCC −2.881 1882264 G C −0.058 4269293 C T −0.6536 7521 G T −2.33 1883369 T G −0.864 4269848 T C −0.9397 7567 A G −0.8127 1883385 T G −0.458 4307601 T A −0.0822 7581 GACAG TGCAC −3.633 1884847 G A −1.139 4308567 G A −1.35 7582 ACAG CCAC −0.3404 1885225 G C −0.402 4326045 CCTC CCTCTC −1.229 7582 A G −0.7807 1886509 T G −1.521 4326068 CGG CGGG −5.355 7584 AG GC −1.499 1917851 C A −1.558 4326082 GTC GTTC −3.101 7585 G C 0.4003 1917972 A G 0.698 4326087 GTA GA −1.776 759857 C A −3.987 1918340 C T −3.252 4326120 GCG GG −3.33 759917 G A −4.024 1918517 GCCC GCCCC −1.223 4326130 CTT CT −2.384 761076 T G −4.001 C 2053589 C T −0.174 4326181 GAA GAAA −1.291 761100 CAATTC CA −4.249 ATGGA 2054231 T C −0.065 4326231 CAA CA −0.276 761128 C G −3.52 2102188 C A −1.708 4326251 TAATTC TAATTC −3.112 761139 C G −0.7744 A AATTCA (SEQ ID NO 023) 2102289 C T −0.474 4326270 CAA CA −3.924 761155 C T −0.2485 2102303 G A −4.059 4326279 ACACC ACACCA −1.362 761314 T C −0.4785 CC 2102417 G A −2.459 4326280 CAC CAAC −4.638 761318 G C −1.192 2102778 C A −4.497 4326292 CTT CT −4.312 761821 C A −3.876 2102849 T C −0.310 4326301 C T −4.688 761828 C G −3.297 2102912 G C −1.954 4326337 G C −1.242 761973 C G −1.178 2133987 C T −0.151 4326350 GAA GA −3.954 762399 G T −3.255 2153870 C G −3.494 4326365 T G −2.6 762477 A G −1.113 2153875 C G −0.906 4326419 GCC GC −4.787 763277 A T −2.56 2154239 T C −0.774 4326426 CAAAAA CAAAAG −4.006 763552 C T −0.8646 G 2154332 A T −4.052 4326463 GAT GT −0.6911 764723 T C −1.501 2154405 C A −0.221 4326493 CAG CG −3.18 764724 T C 0.189 2154695 C G −0.351 4326511 G C −2.298 764841 T C −1.581 2155168 C G −0.483 4326547 CTT CT −2.481 764948 T G −0.2093 2223293 T C −0.022 4326549 T A −2.202 766198 C A −1.605 2279594 G A −0.436 4326577 GCC GA −2.281 781687 A G −0.092 2288703 A C −0.973 4326609 AGG AGGG −0.9033 783699 G A −1.287 2288730 G A −3.934 4326609 AGG AG −1.275 7892 GGCC AGCT −0.4027 2288782 T C −2.325 4326613 GTT GT −1.089 796952 A G −1.197 2288892 AGC AGGC −1.466 4326648 ACC AC −3.165 8075 G T −1.425 2289054 T C −0.394 4326659 AGCTGG AGCTG −2.126 8435 C G −1.786 CG GCGCT GGCG (SEQ ID NO 028) 2289054 T A −3.789 4326663 G A −4.024 8619 T C −3.293 2289068 G T −3.470 4326681 GGAA GGAGAA −2.461 874835 CC CCGC 0.07344 2289077 ACCCG AG −0.967 4326705 GCC GC −5.703 875005 T G 0.02576 2289207 T G −0.179 4326705 GCCA GA −3.879 8861 C G −1.346 2289223 C A −3.633 4326707 C T −2.688 891790 C T 1.379 2518219 T G −0.221 4326717 AGG AGGG −2.412 892272 G A −0.3085 2518864 G C −0.030 4326718 GGCG GGCGC −5.155 9162 C A −0.107 G 2620781 T C −2.061 4326721 GCT GCCT −4.017 931337 T C −3.314 2620945 G T −3.272 4326755 C T −4.292 931398 G A −0.5621 2622158 T G −0.433 4326800 AGCT AGCGCT −3.608 931443 C T −3.251 9846 C G −0.802

TABLE N Para-aminosalicylic acid weighted positions; threshold value: −2.598 POS RN SN W POS RN SN W POS RN SN W 107632 G T −0.028 2288746 CGG CG −0.02798 4327247 G T −0.07262 1487168 G T −0.034 2288824 GCACAC GC −0.07263 4408009 ACC ACCC −0.04536 AATGAT C (SEQ ID NO 029) 1674492 C T −0.032 2518864 G C −0.0006669 490787 C G −0.004473 1718779 A C −0.016 2715009 T A −0.02711 495823 A T −0.03412 1851371 ACCA CCCC −0.032 2726286 G A −0.07263 497128 T G −0.04536 1851371 A C −0.073 2726339 GGT GGG −0.04537 497254 T C −0.07262 1875589 T G −0.007 2832407 A C −0.02353 511208 T C −0.001959 1882264 G C −0.001 3074258 G A −0.04619 576500 A G −0.0462 1883377 G C −0.027 348383 A G −0.0462 615805 T G −0.009441 1883761 T G −0.024 3569297 A C −0.01275 615830 T G −0.01627 1884966 A G −2.058 4124895 A C −0.01907 761140 A G −0.07265 2053589 C T −0.001 4242643 C T 0.001231 764822 G T −0.04536 2102912 G C −0.073 4243331 G T −0.03403 765842 A G −0.02639 2154405 C A −0.003 4249293 A G −0.01863 765882 C G −0.07262 2279349 T G −0.010 4260093 A G −0.02642 797168 T G −0.0462 9162 C A −0.001 9382 G A −0.034

TABLE O Cycloserine weighted positions; threshold value: −1.859 POS RN SN W POS RN SN W 1417272 T G −1.083 404130 T C −0.004 1879405 G T −0.406 4239274 C G −0.401 1883750 T G −0.584 4240664 T G −1.191 1918034 T G −0.451 4243346 A G −0.030 2714913 C T −0.399 4308785 T G −0.022 355709 A C −0.002 4399683 C G −0.003

TABLE P Rifabutin weighted positions; threshold value: −0.605 POS RN SN W 2937852 A C −0.067 4238859 G T −0.283

TABLE Q Levofloxacin weighted positions; threshold value −2.358 POS RN SN W POS RN SN W POS RN SN W 1759252 G T −0.908 1883385 T G −0.2856 4247249 G C −1.37 1850010 C T −0.071 1883750 T G −1.249 4247395 C T −0.3379 1851349 A C −0.332 1884791 T G −0.1154 4249401 T G −0.5473 1876332 GGGC CGGG −1.384 2279407 G A −0.2353 4256011 G A −1.079 1877652 G A −0.340 2288739 G A −0.05764 4399629 C G −0.2104 1878037 T G −0.058 2289082 G A −0.5474 495491 T C −0.5473 1882668 T C −0.859 2693848 G T −0.04647 538621 C G −0.2349 1883369 T G −0.031 346199 G A −0.9649 760314 G T −0.05279 7862 C T −0.547 801174 T C −0.338

Tables A-Q show reference and sample positions and weights for a set of 17 antibiotics. To assess resistance or susceptibility to any of the antibacterial drugs listed, one has to sum the weights in column W for every position in column POS where the sample nucleotide SN is found in the sample instead of reference nucleotide RN and then compare this sum to the threshold provided for this antibiotic in Table 2. If the sum of weights is below or equal to the threshold it is considered resistant, if it is larger than the threshold, the sample is predicted to be susceptible

TABLE 2 Comparison of predicted phenotype to measured phenotype on DNA from clinical isolates. Para- aminosalysic Isoniazid Rifampicin Amikacin Moxifloxacin acid Cycloserine Capreomycin Pyrazinamide Kanamycin Isolate F P F P F P F P F P F P F P F P F P DNA_1 R R R R S S S S R S S S S S S S S S DNA_2 R R R R S S S S S S S S S S R S S S DNA_3 R R R R S S S S S S S S S S R R S S DNA_4 R R R R S S S S S S S S R S R R S S DNA_5 R R R R S S S S S S S S S S R R S S DNA_6 R R R R S S S S R R S S S S R R R S DNA_7 R R R S S S S S S S S S S S R S S S DNA_8 R R R R S S S S S S S S S S R R S S DNA_9 R R R R S S S S S S S S S S R S S S DNA 10 R R R R S S S S S S S S S S R R S S DNA 11 R R R R S S S S S S S S S S S S — R DNA 12 R R R R S S S S S S S S S S R R — S Sequencing data was obtained via targeted sequencing, covering all positions in tables A-Q. F: Phenotype; P: Prediction; R: resistant, S: susceptible, I: intermediary. —: missing measurement 

1. A method for predicting mycobacterial resistance to an antibacterial drug in a patient, comprising the following steps: a. isolating mycobacterial nucleic acid from a sample obtained from said patient; b. a sequencing step, wherein a nucleic acid sample sequence from said mycobacterial nucleic acid is obtained; c. an alignment step, wherein said sample sequence is aligned to a reference sequence, wherein said reference sequence is the sequence NC_000962.3, and wherein the reference sequence comprises a plurality of reference positions, wherein said sequencing step is designed to obtain a sample sequence capable of aligning to all of the positions identified in a table selected from Tables A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P and/or Q; d. a comparison step, wherein said sample sequence is compared to said reference sequence in at least 90% of said plurality of reference positions identified in said table, and wherein for each reference position, it is determined whether the sample sequence value S^(R) is the same as the sample sequence value S^(N) assigned to said position in said table; if S^(R) is the same as S^(N), assigning the value associated to S^(N) in the table as the position weight value to the position; if S^(R) is not the same as S^(N), assigning the value 0 as the position weight value to the position; thereby obtaining a position weight value assigned to each of said reference positions, each of said position weight values being associated to an antibacterial drug designated in said table; e. obtaining a predictor value to predict resistance against said antibacterial drug, by adding all position weight values to obtain the predictor value; f. comparing the predictor value to the threshold value identified in the header of said table, wherein if the predictor value is equal or smaller than the threshold value, resistance to the antibacterial drug is predicted and if the predictor value is larger than the threshold value, susceptibility to the antibacterial drug is predicted.
 2. The method for predicting mycobacterial resistance to an antibacterial drug in a patient according to claim 1, wherein the comparison step comprises comparing said sample sequence to said reference sequence in each of said plurality of reference positions.
 3. The method according to claim 1, wherein resistance or susceptibility to an antibacterial drug is determined for more than one drug by comparing the sample sequence to more than one of Tables A to Q.
 4. The method according to claim 2, wherein drug resistance or susceptibility is determined for six antibacterial drugs, particularly for eight antibacterial drugs, more particularly for ten or twelve, or even for fourteen or sixteen antibacterial drugs.
 5. The method according to claim 3, wherein drug resistance or susceptibility is determined for a plurality of antibacterial drugs including at least one, particularly two, three or even all of ciprofloxacin, para-aminosalycylic acid, cycloserine and rifabutin.
 6. The method according to claim 1, wherein drug resistance is determined for Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, Streptomycin, Ciprofloxacin, Moxifloxacin, Ofloxacin, Amikacin, Capreomycin, Kanamycin, Prothionamide, Ethionamide, Paraaminosalicylic acid, Cycloserine, Rifabutin and Levofloxacin.
 7. A system comprising a sequencing means and a computer programmed to carry out the method of claim
 1. 8. An antibacterial drug selected from Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, Streptomycin, Ciprofloxacin, Moxifloxacin, Ofloxacin, Amikacin, Capreomycin, Kanamycin, Prothionamide, Ethionamide, Paraaminosalicylic acid, Cycloserine, Rifabutin and Levofloxacin for use in treatment of a patient suffering from infection by a mycobacterial strain, wherein susceptibility of said mycobacterial strain is determined by a method according to claim
 1. 9. An antibacterial drug for use in treatment of a patient suffering from infection by a mycobacterial strain, wherein said mycobacterial strain has been determined to be susceptible to said drug by a method according to claim
 1. 